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Zhou Y, Wang X, Tian X, Zhang D, Cui H, Du W, Yang Z, Li J, Li W, Xu J, Duanmu Y, Yu T, Cai F, Li W, Jin Z, Wu W, Huang H. Stealth missiles with precision guidance: A novel multifunctional nano-drug delivery system based on biomimetic cell membrane coating technology. Mater Today Bio 2025; 33:101922. [PMID: 40528836 PMCID: PMC12173624 DOI: 10.1016/j.mtbio.2025.101922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/20/2025] [Accepted: 05/29/2025] [Indexed: 06/20/2025] Open
Abstract
Nanodrug delivery systems (NDDSs) have demonstrated broad application prospects in disease treatment, prevention, and diagnosis due to their nanoscale size advantages and high drug-loading capacity. However, their clinical translation still faces multiple challenges, including rapid clearance by the reticuloendothelial system (RES), nonspecific targeting, and insufficient efficiency in crossing biological barriers. Cell membrane-coated biomimetic delivery systems (CMC-BDS), which integrates natural cell membranes onto nanoparticle (NPs) surfaces, provides nanodrugs with a versatile "biomimetic cloak," representing a highly promising surface engineering strategy. This approach enables nanocarriers to inherit the intrinsic biological properties of different cell sources, endowing them with immune evasion, prolonged circulation, dynamic targeting, biocompatibility, and biodegradability, while supporting the integration of diverse biomedical functions. Furthermore, surface functionalization modifications can enhance their programmability, multifunctionality, and biointerface adaptability, thereby optimizing targeted delivery efficiency and extending in vivo circulation time. This review first outlines the development and key preparation steps of cell membrane coating technology. It then discusses the selection strategies for various cell membrane types-including leukocyte, erythrocyte, platelet, dendritic cell, tumor cell, and bacterial membranes-while comparing their respective advantages and limitations. Finally, the review highlights recent advances in applying cell membrane-coated nanoparticles (CMC-NPs) for treating tumors, ischemic stroke, and inflammatory diseases.
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Affiliation(s)
- Yuyan Zhou
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Xinyue Wang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Xiaorong Tian
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Deyu Zhang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Hanxiao Cui
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wei Du
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhenghui Yang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Jiayu Li
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wanshun Li
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Jiaheng Xu
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Ying Duanmu
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Ting Yu
- Department of Geriatric Medicine, Fujian Provincial Center for Geriatrics, Provincial Hospital Affiliated to Fuzhou University, Fuzhou, 350001, Fujian Province, China
| | - Fengping Cai
- Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Wenhao Li
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan Province, China
| | - Zhendong Jin
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wencheng Wu
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan Province, China
| | - Haojie Huang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
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Meng XM, Wang L, Nikolic-Paterson DJ, Lan HY. Innate immune cells in acute and chronic kidney disease. Nat Rev Nephrol 2025; 21:464-482. [PMID: 40263532 DOI: 10.1038/s41581-025-00958-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/24/2025]
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-related clinical and pathophysiological disorders. Cells of the innate immune system, such as granulocytes and macrophages, can induce AKI through the secretion of pro-inflammatory mediators such as cytokines, chemokines and enzymes, and the release of extracellular traps. In addition, macrophages and dendritic cells can drive the progression of CKD through a wide range of pro-inflammatory and pro-fibrotic mechanisms, and by regulation of the adaptive immune response. However, innate immune cells can also promote kidney repair after acute injury. These actions highlight the multifaceted nature of the way by which innate immune cells respond to signals within the kidney microenvironment, including interaction with the complement and coagulation cascades, cells of the adaptive immune system, intrinsic renal cells and infiltrating mesenchymal cells. The factors and mechanisms that underpin the ability of innate immune cells to contribute to renal injury or repair and to drive the progression of CKD are of great interest for understanding disease processes and for developing new therapeutic approaches to limit AKI and the AKI-to-CKD transition.
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Affiliation(s)
- Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - David J Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre and Monash University Centre for Inflammatory Diseases, Melbourne, Victoria, Australia
| | - Hui-Yao Lan
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
- Departments of Medicine & Therapeutics, the Chinese University of Hong Kong, Hong Kong, and Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China.
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3
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Tang H, Wei Z, Zheng B, Cai Y, Wu P, Wu L, Ma X, Chen Y, Su S, Xu J, Qiao Y, Zhang Y, Miao J, Yu Z, Zhao Y, Xia Z, Zhou R, Liu J, Guo J, Liu Z, Xie Q, Ginhoux F, Zhao L, Li X, Xia B, Wu H, Zhang Y, Zhou T. Rescuing dendritic cell interstitial motility sustains antitumour immunity. Nature 2025:10.1038/s41586-025-09202-9. [PMID: 40562926 DOI: 10.1038/s41586-025-09202-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 05/27/2025] [Indexed: 06/28/2025]
Abstract
The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses1-8. This necessitates the continuous migration of antigen-carrying DCs from the tumour microenvironment (TME) to the tumour draining lymph nodes (tdLNs)7-13. Here, through longitudinal analysis of human and mouse tumours, we observed a progressive decrease in migratory conventional DCs (mig-cDCs) in the tdLNs during tumour progression. This decline compromised tumour-specific T cell priming and subsequent T cell supply to the TME. Using a genome-wide in vivo CRISPR screen, we identified phosphodiesterase 5 (PDE5) and its substrate cyclic guanosine monophosphate (cGMP) as key modulators of DC migration. Advanced tumours disrupted cGMP synthesis in DCs to decrease their motility, while PDE5 perturbation preserved the cGMP pool to restore DC migration. Mechanistically, cGMP enhanced myosin-II activity through Rho-associated factors, extending the paradigm of cGMP-regulated amoeboid migration from Dictyostelium to mammalian immune cells. Pharmacological inhibition of PDE5 using sildenafil restored mig-cDC homing to late-stage tdLNs and sustained antitumour immunity in a DC-dependent manner. Our findings bridge fundamental DC interstitial motility to antitumour immunity, revealing that its disruption in chaotic TME promotes immune evasion, and its enhancement offers a promising direction for DC-centric immunotherapy.
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Affiliation(s)
- Haichao Tang
- School of Medicine, Zhejiang University, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Zongfang Wei
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Bei Zheng
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yumeng Cai
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peihan Wu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Lulu Wu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Xiaohe Ma
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yanqin Chen
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Si Su
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinmin Xu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yu Qiao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Ying Zhang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Juju Miao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Zijing Yu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yaodong Zhao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Zhen Xia
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Rongjing Zhou
- Hangzhou Cancer Hospital, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Jian Liu
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Jufeng Guo
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Xie
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Luming Zhao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Xu Li
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Bing Xia
- Hangzhou Cancer Hospital, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongdeng Zhang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Ting Zhou
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
- School of Medicine, Westlake University, Hangzhou, China.
- School of Life Sciences, Westlake University, Hangzhou, China.
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Alipanahi P, Khosrojerdi A, Pagheh AS, Hatam-Nahavandi K, Ahmadpour E. From pathogen to cure: exploring the antitumor potential of Toxoplasma gondii. Infect Agent Cancer 2025; 20:39. [PMID: 40533757 PMCID: PMC12175340 DOI: 10.1186/s13027-025-00673-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 06/10/2025] [Indexed: 06/22/2025] Open
Abstract
Toxoplasma gondii (T. gondii ), an intracellular protozoan parasite, has attracted significant attention in recent years for its dual role in both promoting and inhibiting cancer. Although traditionally recognized as a potential risk factor for tumor development, particularly in immunocompromised individuals, emerging research suggests that T. gondii may possess anti-cancer properties. This paradox is rooted in the parasite’s ability to modulate the host’s immune system, triggering antitumor immune responses through the activation of immune cells and the secretion of cytokines such as TNF-α and IFN-γ. T. gondii has demonstrated efficacy in reversing tumor-associated immunosuppression, inhibiting angiogenesis, and promoting tumor regression in preclinical models. However, its potential as an immunotherapeutic agent is tempered by the risks associated with administering live parasites, including infection and immune system complications. This article reviews the current understanding of T. gondii impact on cancer and its potential role in cancer therapy. Despite promising preclinical results, challenges remain, including the need for safer therapeutic approaches. Future research should focus on genetically modified or attenuated strains of T. gondii that retain their antitumor capabilities while minimizing risks. Understanding the underlying mechanisms by which T. gondii modulates the tumor microenvironment will be crucial for translating these findings into clinical applications, potentially offering new avenues for cancer treatment.
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Affiliation(s)
- Parisa Alipanahi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Abdol Satar Pagheh
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Kareem Hatam-Nahavandi
- Department of Parasitology and Mycology, School of Medicine, Iranshahr University of Medical Sciences, Sistan and Baluchestan, Iranshahr, Iran
| | - Ehsan Ahmadpour
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Parasitology and Mycology, Tabriz University of Medical Sciences, PO Box: 14155-6446, Tabriz, Iran.
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Wang M, Xiao Y, Miao J, Zhang X, Liu M, Zhu L, Liu H, Shen X, Wang J, Xie B, Wang D. Oxidative Stress and Inflammation: Drivers of Tumorigenesis and Therapeutic Opportunities. Antioxidants (Basel) 2025; 14:735. [PMID: 40563367 DOI: 10.3390/antiox14060735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2025] [Revised: 06/08/2025] [Accepted: 06/12/2025] [Indexed: 06/28/2025] Open
Abstract
As two pivotal regulatory factors in cancer biology, oxidative stress and inflammation interact dynamically through complex network mechanisms to influence tumor initiation, progression, and treatment resistance. Oxidative stress induces genomic instability, oncogenic signaling activation, and tumor microenvironment (TME) remodeling via the abnormal accumulation of reactive oxygen species (ROS) or reactive nitrogen species (RNS). Conversely, inflammation sustains malignant phenotypes by releasing pro-inflammatory cytokines and chemokines and promoting immune cell infiltration. These processes create a vicious cycle via positive feedback loops whereby oxidative stress initiates inflammatory signaling, while the inflammatory milieu further amplifies ROS/RNS production, collectively promoting proliferation, migration, angiogenesis, drug resistance, and immune evasion in tumor cells. Moreover, their crosstalk modulates DNA damage repair, metabolic reprogramming, and drug efflux pump activity, significantly impacting the sensitivity of cancer cells to chemotherapy, radiotherapy, and targeted therapies. This review systematically discusses these advances and the molecular mechanisms underlying the interplay between oxidative stress and inflammation in cancer biology. It also explores their potential as diagnostic biomarkers and prognostic indicators and highlights novel therapeutic strategies targeting the oxidative stress-inflammation axis. The goal is to provide a theoretical framework and translational roadmap for developing synergistic anti-tumor therapies.
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Affiliation(s)
- Meimei Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Yaping Xiao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jie Miao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xin Zhang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Meng Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Longchao Zhu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Hongxin Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xiaoyan Shen
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jihui Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Biao Xie
- Department of Gastroenterology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China
| | - Di Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
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Zhang W, Zhang H, Gao Y, Lei J, Suo C. Fungi and cancer: unveiling the complex role of fungal infections in tumor biology and therapeutic resistance. Front Cell Infect Microbiol 2025; 15:1596688. [PMID: 40557321 PMCID: PMC12185418 DOI: 10.3389/fcimb.2025.1596688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 05/05/2025] [Indexed: 06/28/2025] Open
Abstract
Cancer remains one of the most significant causes of mortality across the world. Despite remarkable advancements made in early detection, therapeutic strategies, and the advent of immunotherapy in recent years, numerous challenges continue to hinder optimal outcomes. The development and progression of cancer are driven not only by genetic and epigenetic alterations within tumor cells but also by dynamic interactions occurring with the surrounding tumor microenvironment (TME). It is a highly complex milieu composed of tumor cells, non-tumor stromal cells, extracellular matrix components, immune cells, blood vessels, and diverse signaling molecules. Emerging evidence underscores the pivotal role of fungi in influencing cancer biology, including initiation, progression, immune evasion, and the modulation of TME. Fungi, which are omnipresent microorganisms, have traditionally been considered opportunistic pathogens. However, recent research highlights their broader impact on host immunity and their potential contributions to cancer pathogenesis. For instance, in patients with cancer, fungal infections not only exacerbate clinical complications but also create conditions conducive to tumor growth, metastasis, and immune escape by altering the immune microenvironment. In addition, fungal-derived metabolites and their interactions with host immune pathways can significantly modulate the efficacy of immunotherapies. These findings have spurred interest in exploring antifungal strategies as adjunctive approaches in cancer management, positioning antifungal therapy as a burgeoning area of oncological research. This review provides an in-depth exploration of the complex interplay between fungi and cancer. It examines the multifaceted role of fungal infections in tumor biology, the mechanisms through which fungi reshape the TME through immune modulation and their influence on immune-evasion strategies and therapeutic resistance. Furthermore, the potential for integrating antifungal therapies into comprehensive cancer treatment regimens has been highlighted, offering insights into novel avenues for improving patient outcomes.
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Affiliation(s)
- Wanli Zhang
- College of Life and Health Science, Northeastern University, Shenyang, Liaoning, China
| | - He Zhang
- Department of Laboratory Animal Center, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Yiru Gao
- College of Life and Health Science, Northeastern University, Shenyang, Liaoning, China
| | - Jianjun Lei
- Department of Laboratory Animal Center, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Chenhao Suo
- Department of Laboratory Animal Center, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
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Talukder A, Rahman MM, Rahi MS, Pountney DL, Wei MQ. Flagellins as Vaccine Adjuvants and Cancer Immunotherapy: Recent Advances and Future Prospects. Immunology 2025. [PMID: 40491306 DOI: 10.1111/imm.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 05/05/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
Flagellin, an essential structural protein of bacterial flagella, has emerged as a potent modulator of both specific and nonspecific immunity, demonstrating significant potential as a vaccine adjuvant and carrier. By inducing the release of pro-inflammatory cytokines like IL-1β, TNF-α, IL-6, IL-8, and IL-12, flagellin activates the innate immune system, enhancing antigen-specific adaptive immune responses mediated by tumour-specific type 1 helper T cells and cytotoxic T cells, thus positioning it as a valuable adjuvant or complementary therapy for various cancers and infectious diseases. This review explores recent strategies, innovations, and clinical applications of flagellin-based immunotherapies, particularly in the context of infectious diseases and cancers. Flagellin from Salmonella typhimurium has been extensively studied as a vaccine adjuvant for diseases like HIV, influenza, dengue, West Nile virus, poultry cholera, and bursal diseases and shows promise in treating lung metastasis, melanoma, colon, and prostate cancers. It has also proven effective against multidrug-resistant bacteria, including Pseudomonas aeruginosa and S. typhimurium. Notably, S. typhimurium flagellin-based vaccines for influenza have progressed to clinical trials. Additionally, flagellins from S. typhi, S. enteritidis, P. aeruginosa, and Escherichia coli are being evaluated as vaccine candidates for plague, malaria, and infections caused by P. aeruginosa and E. coli. In cancer therapy, flagellin-based treatments, especially when combined with tumour antigens, have exhibited the ability to enhance anti-tumour immunity and improve patient outcomes. Other flagellin-based vaccines derived from S. Dublin, S. munchen, and Vibrio vulnificus have been employed in the treatment of prostate, lung, liver, breast, cervical, and colorectal cancers, as well as lymphoma, melanoma, and radiation-induced mucositis. Mobilan, a recombinant non-replicating adenovirus vector expressing Salmonella flagellin, is currently in a phase Ib clinical trial for prostate cancer. Overall, bacterial flagellin treatments are generally safe, well-tolerated, and associated with minimal side effects, making them a promising option for managing infectious diseases and cancers.
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Affiliation(s)
- Asma Talukder
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Md Mijanur Rahman
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Md Sifat Rahi
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Dean L Pountney
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Ming Q Wei
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
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8
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Lin J, Li Y, Sun J. Modulating immune cells within pancreatic ductal adenocarcinoma via nanomedicine. Essays Biochem 2025:EBC20243001. [PMID: 40420798 DOI: 10.1042/ebc20243001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/28/2025] [Indexed: 05/28/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense extracellular matrix (ECM) and a uniquely immunosuppressive tumor microenvironment (TME), which together form a formidable barrier that hinders deep drug penetration, limiting the efficacy of conventional therapies and leading to poor patient outcomes. Nanocarrier technology emerges as a promising strategy to improve treatment efficacy in PDAC. Nanocarriers can not only improve drug penetration through their adjustable physicochemical properties but also effectively regulate immune cell function in pancreatic cancer TME and promote anti-tumor immune response. This mini-review discusses the effects of nanocarriers on the immune microenvironment of PDAC, analyzing their mechanisms in modulating immune cells, overcoming ECM barriers, and reshaping the TME.
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Affiliation(s)
- Junyi Lin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
| | - Ying Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
| | - Jingjing Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
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Elsabbagh RA, Abdelhady G, Urlaub D, Sandusky M, Khorshid O, Gad MZ, Abou-Aisha K, Watzl C, Rady M. N 6-methyladenosine RNA base modification regulates NKG2D-dependent and cytotoxic genes expression in natural killer cells. BMC Med Genomics 2025; 18:91. [PMID: 40389988 PMCID: PMC12090489 DOI: 10.1186/s12920-025-02147-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/17/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Breast cancer (BC) is the most commonly diagnosed cancer in women. N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian mRNAs and plays a crucial role in various biological processes. However, its function in Natural killer (NK) cells in BC remains unclear. NK cells are essential for cancer immunosurveillance. This study aims to assess m6A levels in transcripts involved in the NKG2D cytotoxicity signaling pathway in NK cells of BC patients compared to controls and find out its impact on mRNA levels. Additionally, it evaluates how deliberately altering m6A levels in NK cells affects mRNA and protein expression of NKG2D pathway genes and NK cell functionality. METHODS m6A methylation in transcripts of NKG2D-pathway-related genes in BC patients and controls was determined using methylated RNA immunoprecipitation-reverse transcription-PCR (MERIP-RT-PCR). To deliberately alter m6A levels in primary cultured human NK cells, the m6A demethylases, FTO and ALKBH5, were knocked out using the CRISPR-CAS9 system, and FTO was inhibited using Meclofenamic acid (MA). The impact of m6A alteration on corresponding mRNA and protein levels was assessed using RT-qPCR and Western blot analysis or flow cytometry, respectively. Additionally, NK cell functionality was evaluated through degranulation and 51Cr release cytotoxicity assays. RESULTS Transcripts of NKG2D, an activating receptor that detects stressed non-self tumour cells, had significantly higher m6A levels in the 3' untranslated region (3'UTR) accompanied by a marked reduction in their corresponding mRNA levels in BC patients compared to controls. Conversely, transcripts of ERK2 and PRF1 exhibited significantly lower m6A levels escorted with higher mRNA expression in BC patients relative to controls. The mRNA levels of PI3K, PAK1 and GZMH were also significantly elevated in BC patients. Furthermore, artificially increasing transcripts' m6A levels via MA in cultured primary NK cells reduced mRNA levels of NKG2D pathway genes and death receptor ligands but did not affect protein expression or NK cell functionality. CONCLUSION Transcripts with higher m6A levels in the 3'UTR region were less abundant, and vice versa. However, changes in mRNA levels of the target genes didn't impact their corresponding protein levels or NK cell functionality.
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Affiliation(s)
- Raghda A Elsabbagh
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Ghada Abdelhady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Doris Urlaub
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany
| | - Mina Sandusky
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany
| | - Ola Khorshid
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Khaled Abou-Aisha
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Carsten Watzl
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany.
| | - Mona Rady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt.
- Faculty of Biotechnology, German International University, New Administrative Capital, Egypt.
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10
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Yang Y, Zhu L, Xu Y, Liang L, Liu L, Chen X, Li H, Liu H. The progress and prospects of targeting the adenosine pathway in cancer immunotherapy. Biomark Res 2025; 13:75. [PMID: 40390144 PMCID: PMC12090549 DOI: 10.1186/s40364-025-00784-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 04/26/2025] [Indexed: 05/21/2025] Open
Abstract
Despite the notable success of cancer immunotherapy, its effectiveness is often limited in a significant proportion of patients, highlighting the need to explore alternative tumor immune evasion mechanisms. Adenosine, a key metabolite accumulating in hypoxic tumor regions, has emerged as a promising target in oncology. Inhibiting the adenosinergic pathway not only inhibits tumor progression but also holds potential to enhance immunotherapy outcomes. Multiple therapeutic strategies targeting this pathway are being explored, ranging from preclinical studies to clinical trials. This review examines the complex interactions between adenosine, its receptors, and the tumor microenvironment, proposing strategies to target the adenosinergic axis to boost anti-tumor immunity. It also evaluates early clinical data on pharmacological inhibitors of the adenosinergic pathway and discusses future directions for improving clinical responses.
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Affiliation(s)
- Yuying Yang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Lin Zhu
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yantao Xu
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Long Liang
- Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Li Liu
- Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Xiang Chen
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Hui Li
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Hong Liu
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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11
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Hushmandi K, Imani Fooladi AA, Reiter RJ, Farahani N, Liang L, Aref AR, Nabavi N, Alimohammadi M, Liu L, Sethi G. Next-generation immunotherapeutic approaches for blood cancers: Exploring the efficacy of CAR-T and cancer vaccines. Exp Hematol Oncol 2025; 14:75. [PMID: 40382583 DOI: 10.1186/s40164-025-00662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/25/2025] [Indexed: 05/20/2025] Open
Abstract
Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Liping Liang
- Guangzhou Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | | | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China.
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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12
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Chao CJ, Zhang E, Trinh DN, Udofa E, Lin H, Silvers C, Huo J, He S, Zheng J, Cai X, Bao Q, Zhang L, Phan P, Elgendy SM, Shi X, Burdette JE, Lee SSY, Gao Y, Zhang P, Zhao Z. Integrating antigen capturing nanoparticles and type 1 conventional dendritic cell therapy for in situ cancer immunization. Nat Commun 2025; 16:4578. [PMID: 40379691 DOI: 10.1038/s41467-025-59840-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 05/02/2025] [Indexed: 05/19/2025] Open
Abstract
Eliciting a robust immune response against tumors is often hampered by the inadequate presence of effective antigen presenting cells and their suboptimal ability to present antigens within the immunosuppressive tumor microenvironment. Here, we report a cascade antigen relay strategy integrating antigen capturing nanoparticles (AC-NPs) and migratory type 1 conventional dendritic cells (cDC1s), named Antigen Capturing nanoparticle Transformed Dendritic Cell therapy (ACT-DC), to facilitate in situ immunization. AC-NPs are engineered to capture antigens directly from the tumor and facilitate their delivery to adoptively transferred migratory cDC1s, enhancing antigen presentation to the lymph nodes and reshaping the tumor microenvironment. Our findings suggest that ACT-DC improves in situ antigen collection, triggers a robust systemic immune response without the need for exogenous antigens, and transforms the tumor environment into a more "immune-hot" state. In multiple tumor models including colon cancer, melanoma, and glioma, ACT-DC in combination with immune checkpoint inhibitors eliminates primary tumors in 50-100% of treated mice and effectively rejects two separate tumor rechallenges. Collectively, ACT-DC could provide a broadly effective approach for in situ cancer immunization and tumor microenvironment modulation.
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Affiliation(s)
- Chih-Jia Chao
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Endong Zhang
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Duong N Trinh
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Edidiong Udofa
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Hanchen Lin
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Caylee Silvers
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jiawei Huo
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Shan He
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Jingtian Zheng
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Xiaoying Cai
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Qing Bao
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Luyu Zhang
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Philana Phan
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Sara M Elgendy
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Xiangqian Shi
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
| | - Joanna E Burdette
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, Chicago, IL, USA
| | - Steve Seung-Young Lee
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, Chicago, IL, USA
| | - Yu Gao
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, Chicago, IL, USA
| | - Peng Zhang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Zongmin Zhao
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA.
- University of Illinois Cancer Center, Chicago, IL, USA.
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13
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Li Z, Wang Y, Mo F, Wolter T, Hong R, Barrett A, Richmond N, Liu F, Chen Y, Yang X, Dempsey L, Hu Q. Engineering pyroptotic vesicles as personalized cancer vaccines. NATURE NANOTECHNOLOGY 2025:10.1038/s41565-025-01931-2. [PMID: 40379868 DOI: 10.1038/s41565-025-01931-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 03/31/2025] [Indexed: 05/19/2025]
Abstract
Tumour vaccines are designed to stimulate the host's immune system against existing tumours or tumour recurrence. However, individual differences, tumour heterogeneity and side effects hinder the applications of current tumour vaccines and require the development of personalized cancer vaccines. To overcome these challenges, we engineered pyroptotic vesicles-extracellular vesicles formed during tumour cell pyroptosis-as a tumour vaccine platform. The extracted pyroptotic vesicles possess abundant tumour antigens and potent immune-stimulating ability and, loaded into a biocompatible hydrogel, they can be implanted into post-surgical tumour cavities to prevent tumour recurrence. The pyroptotic-vesicle-based vaccine outperforms both exosome- and apoptotic-body-based vaccines in inhibiting tumour recurrence and metastasis in different post-surgical mouse models. Mechanistic studies reveal that the pyroptotic-vesicle-based vaccine could stimulate robust antigen-specific dendritic cell and T cell immune responses against both artificial OVA antigens and cancer neoantigens. In sum, our vaccine platform can be tailored to stimulate robust antitumour immune responses for treating individual cancer patients.
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Affiliation(s)
- Zhaoting Li
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Yixin Wang
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Fanyi Mo
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Tyler Wolter
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Rachel Hong
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Allie Barrett
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Nathaniel Richmond
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Fengyuan Liu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Yu Chen
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Xicheng Yang
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Lauren Dempsey
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Quanyin Hu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
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14
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Wang X, Liu Y, Jiang Y, Li Q. Tumor-derived exosomes as promising tools for cancer diagnosis and therapy. Front Pharmacol 2025; 16:1596217. [PMID: 40444049 PMCID: PMC12119533 DOI: 10.3389/fphar.2025.1596217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
Mounting evidences indicated that cancer cell-derived exosomes (TDEs) contribute to cancer progression and metastasis by reshaping the tumor microenvironment (TME) and interfering immunity response. TDEs contain unique biomolecular cargo, consisting of protein, nucleic acid, and lipids. In recent years, TDEs have been used as potential disease therapeutics and diagnosis biomarkers and prime candidates as delivery tools for cancer treatment. In the present review, we firstly summarized TDEs biogenesis and characteristic. Also, the role of TDEs in cancer cell metastasis and invasiveness, drug resistance, and immunosuppression was mentioned via cell-cell communication. Additionally, we concluded the current strategies for TDE-based cancer therapy, including TDEs inhibition and clearance, usage as therapeutic drug delivery vector and cancer vaccines. Furthermore, combination therapy with engineered TDEs were summarized, such as radiotherapy, photodynamic therapy, photothermal therapy, and sonodynamic therapy. Consequently, the above opens up novel and interesting opportunities for cancer diagnosis and prognosis based on TDEs, which is prospective to accelerate the clinical translation of TDEs for cancer therapy.
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Affiliation(s)
- Xirui Wang
- Department of Biomedical Engineering, School of Medical Imaging Xuzhou Medical University, Xuzhou, China
| | - Yanfang Liu
- Department of Central Laboratory, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Yaowen Jiang
- Department of Biomedical Engineering, School of Medical Imaging Xuzhou Medical University, Xuzhou, China
| | - Qinghua Li
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
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15
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Giram P, Md Mahabubur Rahman K, Aqel O, You Y. In Situ Cancer Vaccines: Redefining Immune Activation in the Tumor Microenvironment. ACS Biomater Sci Eng 2025; 11:2550-2583. [PMID: 40223683 DOI: 10.1021/acsbiomaterials.5c00121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.
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Affiliation(s)
- Prabhanjan Giram
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Kazi Md Mahabubur Rahman
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Osama Aqel
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Youngjae You
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
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16
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Zhao X, Zhong Q, Abudouaini N, Zhao Y, Zhang J, Tan G, Miao G, Wang X, Liu J, Pan Y, Wang X. Switchable Nanophotosensitizers as Pyroptosis Inducers for Targeted Boosting of Antitumor Photoimmunotherapy. Biomacromolecules 2025; 26:3065-3083. [PMID: 40200409 DOI: 10.1021/acs.biomac.5c00140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Photodynamic therapy (PDT) has emerged as a promising modality for cancer treatment, but its clinical application is constrained by unexpected phototoxicity arising from nonspecific photosensitizer activation and their "always-on" nature. Herein, we developed a switchable nanophotosensitizer, poly(cation-π) nanoparticles (NP), which achieves supramolecular assembly through cation-π interactions. By coupling choline cationic moieties with aromatic photosensitizers (ZnPc), the polymer facilitates self-assembly driven by cation-π interactions for NP engineering. Surprisingly, the photoactivity of ZnPc was completely quenched upon complexation via cation-π interactions, thereby significantly avoiding skin phototoxicity. Upon targeting tumor cells, NP undergoes a GSH-responsive degradation process that weakens cation-π interactions, leading to spontaneous restoration of photoactivity and amplifying tumor immunogenic pyroptosis. In vivo studies demonstrated that NP achieved a high tumor inhibition rate of 84% while effectively avoiding skin phototoxicity. This work provides a novel perspective for enhancing the safety and efficacy of PDT-based tumor treatment.
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Affiliation(s)
- Xiaoxi Zhao
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Qinjie Zhong
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Naibijiang Abudouaini
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yan Zhao
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jibin Zhang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Guozhu Tan
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Guifeng Miao
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
- Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Xiaowu Wang
- Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Jianqiang Liu
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Ying Pan
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Xiaorui Wang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China
- Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China
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17
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Li JY, Jiang RY, Wang J, Wang XJ. Advances in mRNA vaccine therapy for breast cancer research. Discov Oncol 2025; 16:673. [PMID: 40327249 PMCID: PMC12055746 DOI: 10.1007/s12672-025-02542-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Breast cancer represents the most prevalent cancer among women globally, constituting approximately 30% of newly diagnosed female malignancies and serving as the second leading cause of cancer-related mortality, accounting for 11.6% of deaths. Despite notable advancements in survival rates and quality of life for breast cancer patients over recent decades-achieved through interventions such as surgery, chemotherapy, radiotherapy, and endocrine therapy-there remains an urgent need for novel therapeutic strategies. This necessity arises from challenges associated with recurrence, metastasis, and drug resistance. The COVID-19 pandemic has accelerated the development of Messenger RNA (mRNA) vaccines at an unprecedented pace, and as a novel form of precision immunotherapy, mRNA vaccines are increasingly being recognized for their potential in cancer treatment. mRNA vaccines efficiently produce antigens within the cytoplasm, specifically activating the immune system to target tumor cells while minimizing the risk of T-cell tolerance. Therefore, mRNA vaccines have emerged as a promising approach in cancer immunotherapy. This review systematically examines the principles, mechanisms, advantages, key targets, and recent progress in mRNA vaccine therapy for breast cancer. Furthermore, it discusses current challenges and suggests potential directions for future research.
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Affiliation(s)
- Jia-Ying Li
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Rui-Yuan Jiang
- Department of Graduate Student, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
| | - Jia Wang
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Xiao-Jia Wang
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
- Department of Medical Oncology(Breast), Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
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18
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Jeng LB, Shih FY, Liao YW, Shyu WC, Teng CF. Hypoxic tumor cell line lysate-pulsed dendritic cell vaccine exhibits better therapeutic effects on hepatocellular carcinoma. Br J Cancer 2025; 132:837-848. [PMID: 40050434 PMCID: PMC12041587 DOI: 10.1038/s41416-025-02975-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/03/2025] [Accepted: 02/26/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Dendritic cell (DC) vaccine is a promising immunotherapy for hepatocellular carcinoma (HCC) via triggering antigen-specific anti-tumor immunity. Hypoxia contributes to higher level and broader spectrum of antigen expression in tumor cells. METHODS This study aims to compare immunological activity and therapeutic efficacy between hypoxic and normoxic HCC cell line lysate-pulsed DC vaccines. RESULTS The results showed that hypoxic HCC cell line lysate-pulsed DC vaccines exhibited a stronger activity in producing interleukin-12 and promoting T cell proliferation and cytotoxicity in vitro. In HCC mice, hypoxic HCC cell line lysate-pulsed DC vaccines displayed a better efficacy in improving survival time and tumor volume and inducing intratumoral cytotoxic T cell infiltration and activation as well as tumor cell apoptosis. Adenylate kinase 4-derived antigens were important for hypoxic HCC cell line lysate-pulsed DC vaccine-elicited T cell killing. CONCLUSIONS In conclusion, this study demonstrated hypoxic HCC cell line lysate-pulsed DC vaccine as a potential therapeutic strategy for HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan, ROC
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
- Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan, ROC
- School of Medicine, China Medical University, Taichung, Taiwan, ROC
| | - Fu-Ying Shih
- Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, Taiwan, ROC
| | - Yu-Wen Liao
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC
| | - Woei-Cherng Shyu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC
- Translational Medicine Research Center, China Medical University Hospital, Taichung, 404, Taiwan, ROC
- Department of Neurology, China Medical University Hospital, Taichung, Taiwan, ROC
- Department of Occupational Therapy, Asia University, Taichung, Taiwan, ROC
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan, ROC.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan, ROC.
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19
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Hu MH, Fan D, Tu HF, Tsai YC, He L, Zhou Z, Cheng M, Xing D, Wang S, Wu A, Wu TC, Hung CF. Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity. Gene Ther 2025; 32:277-286. [PMID: 39472678 DOI: 10.1038/s41434-024-00497-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 05/28/2025]
Abstract
Dendritic cells (DCs) constitute a distinct type of immune cell found within tumors, serving a central role in mediating tumor antigen-specific immunity against cancer cells. Frequently, DC functions are dysregulated by the immunosuppressive signals present within the tumor microenvironment (TME). Consequently, DC manipulation holds great potential to enhance the cytotoxic T cell response against cancer diseases. One strategy involves administering Fms-like tyrosine kinase receptor 3 ligand (Flt3L), a vitally important cytokine for DC development. In this current study, the electroporation-mediated delivery of a novel albumin-fused Flt3L DNA (alb-Flt3L DNA) demonstrated the ability to induce an anti-tumor immune response. This albumin fusion construct possesses more persistent bioactivity in targeted organs. Furthermore, TC-1-bearing-C57BL/6 mice receiving alb-Flt3L DNA treatment presented better tumor control and superior survival. Cellular analysis revealed that alb-Flt3L DNA administration promoted robust DC and cDC1 expansion. In addition, increased levels of IFN-γ-secreting CD8+ lymphocytes were found in correlation to greater cDC1 population. Moreover, the toxicity of alb-Flt3L administration is limited. Collectively, our data showcases a novel DC-based immunotherapy using electroporation to administer alb-Flt3L DNA.
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Affiliation(s)
- Ming-Hung Hu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
- Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC
| | - Darrell Fan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hsin-Fang Tu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ya-Chea Tsai
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Liangmei He
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zhicheng Zhou
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michelle Cheng
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Deyin Xing
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Suyang Wang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexis Wu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - T C Wu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Molecular Microbiology and Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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20
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He Y, Tian T, Li Y, Zeng Y, Wang X, Qian L, Tian T, Jiang M, Li L. From neglect to necessity: the role of innate immunity in cutaneous squamous cell carcinoma therapy. Front Immunol 2025; 16:1570032. [PMID: 40352926 PMCID: PMC12061915 DOI: 10.3389/fimmu.2025.1570032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/03/2025] [Indexed: 05/14/2025] Open
Abstract
As the second most common non-melanoma skin cancer, cutaneous squamous cell carcinoma (cSCC) has experienced a significant increase in incidence. Although clinical detection is relatively easy, a considerable number of patients are diagnosed at an advanced stage, featuring local tissue infiltration and distant metastasis. Cemiplimab, along with other immune checkpoint inhibitors, enhances T cell activation by blocking the PD-1 pathway, resulting in notable improvements in clinical outcomes. Nonetheless, approximately 50% of the patients with advanced cSCC remain unresponsive to this therapeutic approach. It emphasizes the importance of finding innovative therapeutic targets and strategies to boost the success of immunotherapy across a wider range of patients. Therefore, we focused on frequently neglected functions of innate immune cells. Emerging evidence indicates that innate immune cells exhibit considerable heterogeneity and plasticity, fundamentally contributing to tumor initiation and development. The identification and eradication of cancer cells, along with the modulation of adaptive immune responses, are essential roles of these cells. Consequently, targeting innate immune cells to activate anti-tumor immune responses presents significant potential for enhancing immunotherapeutic strategies in cSCC.
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Affiliation(s)
- Yong He
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Ting Tian
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yuancheng Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yong Zeng
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiaoke Wang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Leqi Qian
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Tian Tian
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Mingjun Jiang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Liming Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
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21
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Huang L, Li X, Zhang H, Liu F, Dai Z, Xiao F, Wang L, Wang Z. Zinc Ion-Coordinated Sericin Calcium Phosphate Nanovaccines Induce Hyperactive Dendritic Cells and Synergistic Activation of T Cells for Cancer Immunotherapy. ACS NANO 2025; 19:13906-13926. [PMID: 40177975 DOI: 10.1021/acsnano.4c17491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Peptide-based neoantigen vaccines are promising cancer immunotherapy strategies because of their capability to induce durable tumor-specific immune responses. However, insufficient neoantigen-specific T-lymphocyte activation greatly limits their clinical efficacy. Here, we developed sericin-coordinated zinc ion-modified calcium phosphate (CP) nanovaccines that codeliver tumor antigen peptides and a Toll-like receptor 9 agonist (SZCP/APs-CpG) for potentiating antigen-specific T cell immunity. SZCP/APs-CpG nanovaccines could yield efficient codelivery of antigen peptides and adjuvants to dendritic cells (DCs) in draining lymph nodes (dLNs), induce hyperactive DCs depending on the inflammasome-dependent interleukin-1β secretion, and coordinate the released Zn2+-induced T cell activation to elicit robust and durable antigen-specific T cell immune responses. Vaccination with SZCP/APs-CpG exhibited potent anticancer efficacy and superior safety in multiple murine cancer models and significantly protected against B16-OVA tumor rechallenge and eradicated orthotopic colon cancer in mice when combined with immune checkpoint blockade. Thus, our work presents an efficient and versatile nanovaccine platform for boosting antigen-specific T cell activation for cancer immunotherapy.
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Affiliation(s)
- Lei Huang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Xinbo Li
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Hongyan Zhang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Feng Liu
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Zheng Dai
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Fang Xiao
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lin Wang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
| | - Zheng Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-Disciplinary Translational Research, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China
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22
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Kalemoglu E, Jani Y, Canaslan K, Bilen MA. The role of immunotherapy in targeting tumor microenvironment in genitourinary cancers. Front Immunol 2025; 16:1506278. [PMID: 40260236 PMCID: PMC12009843 DOI: 10.3389/fimmu.2025.1506278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
Genitourinary (GU) cancers, including renal cell carcinoma, prostate cancer, bladder cancer, and testicular cancer, represent a significant health burden and are among the leading causes of cancer-related mortality worldwide. Despite advancements in traditional treatment modalities such as chemotherapy, radiotherapy, and surgery, the complex interplay within the tumor microenvironment (TME) poses substantial hurdles to achieving durable remission and cure. The TME, characterized by its dynamic and multifaceted nature, comprises various cell types, signaling molecules, and the extracellular matrix, all of which are instrumental in cancer progression, metastasis, and therapy resistance. Recent breakthroughs in immunotherapy (IO) have opened a new era in the management of GU cancers, offering renewed hope by leveraging the body's immune system to combat cancer more selectively and effectively. This approach, distinct from conventional therapies, aims to disrupt cancer's ability to evade immune detection through mechanisms such as checkpoint inhibition, therapeutic vaccines, and adoptive cell transfer therapies. These strategies highlight the shift towards personalized medicine, emphasizing the importance of understanding the intricate dynamics within the TME for the development of targeted treatments. This article provides an in-depth overview of the current landscape of treatment strategies for GU cancers, with a focus on IO targeting the specific cell types of TME. By exploring the roles of various cell types within the TME and their impact on cancer progression, this review aims to underscore the transformative potential of IO strategies in TME targeting, offering more effective and personalized treatment options for patients with GU cancers, thereby improving outcomes and quality of life.
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Affiliation(s)
- Ecem Kalemoglu
- Department of Internal Medicine, Rutgers-Jersey City Medical Center, Jersey City, NJ, United States
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Türkiye
| | - Yash Jani
- Medical College of Georgia, Augusta, GA, United States
| | - Kubra Canaslan
- Department of Medical Oncology, Dokuz Eylul University, Izmir, Türkiye
| | - Mehmet Asim Bilen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
- Department of Urology, Emory University School of Medicine, Atlanta, GA, United States
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23
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Oyama K, Nakata K, Abe T, Hirotaka K, Fujimori N, Kiyotani K, Iwamoto C, Ikenaga N, Morisaki S, Umebayashi M, Tanaka H, Koya N, Nakagawa S, Tsujimura K, Yoshimura S, Onishi H, Nakamura Y, Nakamura M, Morisaki T. Neoantigen peptide-pulsed dendritic cell vaccine therapy after surgical treatment of pancreatic cancer: a retrospective study. Front Immunol 2025; 16:1571182. [PMID: 40248703 PMCID: PMC12004129 DOI: 10.3389/fimmu.2025.1571182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/10/2025] [Indexed: 04/19/2025] Open
Abstract
Introduction Pancreatic cancer shows very poor prognosis and high resistance to conventional standard chemotherapy and immunotherapy; therefore, the development of new breakthrough therapies is highly desirable. Method We retrospectively evaluated the safety and efficacy of neoantigen peptide-pulsed dendritic cell (Neo-P DC) vaccine therapy after surgical treatment of pancreatic cancer. Result The result showed induction of neoantigen-specific T cells in 13 (81.3%) of the 16 patients who received Neo-P DC vaccines. In survival analysis of the nine patients who received Neo-P DC vaccines after recurrence, longer overall survival was observed in patients with neoantigen-specific T cell induction than those without T cell induction. Notably, only one of the seven patients who received Neo-P DC vaccines as adjuvant setting developed recurrence, and no patient died during median follow-up 61 months after surgery (range, 25-70 months). Furthermore, TCR repertoire analyses were performed in a case treated with Neo-P DC vaccine combined with long and short peptides, and one significantly dominant clone induced by the long peptide was detected among CD4+ T cell populations. Discussion The present study suggests the feasibility and efficacy of Neo-P DC vaccine therapy after surgical treatment of pancreatic cancer in both postoperative recurrence cases and adjuvant setting. A case analysis suggests the importance of combination with long peptides targeting CD4+ T cell.
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Affiliation(s)
- Koki Oyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiya Abe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kento Hirotaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nao Fujimori
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuma Kiyotani
- Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayo Umebayashi
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Hiroto Tanaka
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Norihiro Koya
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Shinichiro Nakagawa
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Kenta Tsujimura
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Sachiko Yoshimura
- Corporate Headquarters, Cancer Precision Medicine Inc., Kawasaki, Japan
| | - Hideya Onishi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Nakamura
- Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
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24
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Wu G, Zhong C, Tian X, Zha L, Hou L, Feng X. Emerging roles of hyaluronic acid hydrogels in cancer treatment and wound healing: A review. Int J Biol Macromol 2025; 303:140442. [PMID: 39880244 DOI: 10.1016/j.ijbiomac.2025.140442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/03/2025] [Accepted: 01/27/2025] [Indexed: 01/31/2025]
Abstract
Hyaluronic acid (HA)-derived hydrogels demonstrate a significant development in the biomedical uses, especially in cancer treatment and wound repair. Cancer continues to be one of the leading causes of death worldwide, with current therapies frequently impeded by lack of specificity, side effects, and the emergence of resistance. HA hydrogels, characterized by their distinctive three-dimensional structure, hydrophilic nature, and biocompatibility, develop an advanced platform for precise drug delivery, improving therapeutic results while minimizing systemic toxicity. These hydrogels facilitate the controlled release of drugs, genes, and various therapeutic substances, enhancing the effectiveness of chemotherapy, radiotherapy, and immunotherapy. Additionally, they can be designed to react to stimuli such as pH, light, and magnetic fields, enhancing their therapeutic capabilities. In the process of wound healing, the hydrophilic and porous characteristics of HA hydrogels establish a moist environment encouraging cell growth and contributes to the tissue recovery. By imitating the extracellular matrix, they promote tissue regeneration, improve angiogenesis, and influence immune reactions. This review examines the various functions of HA-based hydrogels in cancer treatment and wound healing, highlighting their advancement, applications, and ability to change existing therapeutic methods in these important health sectors.
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Affiliation(s)
- Gang Wu
- Department of Hepatobiliary Pancreatic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Chunyan Zhong
- Department of Ultrasound, Chongqing Health Center for Women and Children, Chongqing, China
| | - Xiaohui Tian
- Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Lisha Zha
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan, PR China.
| | - Lingmi Hou
- Department of Breast Surgery, Sichuan Clinical Research Center for Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610041, Sichuan, China.
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, No. 89 Xiguan Road, Gaozhou 525299, Guangdong, China.
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25
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Ziogou A, Giannakodimos A, Giannakodimos I, Schizas D, Charalampakis N. Effect of Helicobacter Pylori infection on immunotherapy for gastrointestinal cancer: a narrative review. Immunotherapy 2025; 17:355-368. [PMID: 40087147 PMCID: PMC12045566 DOI: 10.1080/1750743x.2025.2479410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025] Open
Abstract
Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.
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Affiliation(s)
- Afroditi Ziogou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
| | | | - Ilias Giannakodimos
- Departement of Urology, Attikon University Hospital of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Poudel K, Ji Z, Njauw CN, Rajadurai A, Bhayana B, Sullivan RJ, Kim JO, Tsao H. Fabrication and functional validation of a hybrid biomimetic nanovaccine (HBNV) against Kit K641E -mutant melanoma. Bioact Mater 2025; 46:347-364. [PMID: 39834347 PMCID: PMC11742834 DOI: 10.1016/j.bioactmat.2024.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/03/2024] [Accepted: 12/20/2024] [Indexed: 01/22/2025] Open
Abstract
Cancer nanovaccines hold the promise for personalization, precision, and pliability by integrating all the elements essential for effective immune stimulation. An effective immune response requires communication and interplay between antigen-presenting cells (APCs), tumor cells, and immune cells to stimulate, extend, and differentiate antigen-specific and non-specific anti-tumor immune cells. The versatility of nanomedicine can be adapted to deliver both immunoadjuvant payloads and antigens from the key players in immunity (i.e., APCs and tumor cells). The imperative for novel cancer medicine is particularly pressing for less common but more devastating KIT-mutated acral and mucosal melanomas that are resistant to small molecule c-kit and immune checkpoint inhibitors. To overcome this challenge, we successfully engineered nanotechnology-enabled hybrid biomimetic nanovaccine (HBNV) comprised of membrane proteins (antigens to activate immunity and homing/targeting ligand to tumor microenvironment (TME) and lymphoid organs) from fused cells (of APCs and tumor cells) and immunoadjuvant. These HBNVs are efficiently internalized to the target cells, assisted in the maturation of APCs via antigens and adjuvant, activated the release of anti-tumor cytokines/inhibited the release of immunosuppressive cytokine, showed a homotypic effect on TME and lymph nodes, activated the anti-tumor immune cells/downregulated the immunosuppressive immune cells, reprogram the tumor microenvironment, and showed successful anti-tumor therapeutic and prophylactic effects.
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Affiliation(s)
- Kishwor Poudel
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhenyu Ji
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ching-Ni Njauw
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Anpuchchelvi Rajadurai
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Brijesh Bhayana
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ryan J. Sullivan
- Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hensin Tsao
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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27
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Li J, Yu S, Rao M, Cheng B. Tumor-derived extracellular vesicles: key drivers of immunomodulation in breast cancer. Front Immunol 2025; 16:1548535. [PMID: 40103824 PMCID: PMC11914124 DOI: 10.3389/fimmu.2025.1548535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/20/2025] [Indexed: 03/20/2025] Open
Abstract
Breast cancer (BC) remains a significant global health challenge characterized by its heterogeneity and treatment complexities. Extracellular vesicles (EVs) are small membranous particles released by cells, facilitating intercellular communication by transporting bioactive molecules such as proteins, lipids, and nucleic acids. Tumor-derived EVs have emerged as pivotal regulators in the tumor microenvironment (TME) and drivers of BC progression. These EVs carry diverse cargoes of bioactive molecules, influencing critical processes such as immune modulation, angiogenesis, and metastasis. By altering the behaviors of immune cells including macrophages, dendritic cells, and T cells, tumor-derived EVs contribute to immune evasion and tumor growth. Furthermore, Tumor-derived EVs play a role in mediating drug resistance, impacting the effectiveness of therapeutic interventions. Understanding the multifaceted roles of BC tumor-derived EVs is essential for the development of innovative therapeutic strategies. Targeting pathways mediated by EVs holds promise for enhancing the efficacy of cancer treatments and improving patient outcomes. This comprehensive review provides insights into the intricate interactions of tumor-derived EVs in immune modulation and BC progression, highlighting potential therapeutic targets and avenues for novel cancer therapies.
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Affiliation(s)
- Jieming Li
- Traditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, China
- Department of Polysaccharides and Drugs, Henan Key Laboratory of Chinese Medicine, Zhengzhou, China
| | - Shuo Yu
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Rao
- Nursing Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bomin Cheng
- Chinese Medicine Health Management Center, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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28
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Qian X, Yi W, Yan W, Cai Y, Hu S, Yan D, Zhao Z, Li R, Wang L, Xu H, Li Y. Cryo-Shocked Tumor-Reprogrammed Sonosensitive Antigen-Presenting Cells Improving Sonoimmunotherapy via T Cells and NK Cells Immunity. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2413289. [PMID: 39955715 DOI: 10.1002/adma.202413289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 02/05/2025] [Indexed: 02/17/2025]
Abstract
Ultrasound therapy has turned up as a noninvasive multifunctional tool for cancer immunotherapy. However, the insufficient co-stimulating molecules and loss of peptide-major histocompatibility complex I (MHC-I) expression on tumor cells lead to poor therapy of sonoimmunotherapies. Herein, this work develops a sonosensitive system to augment MHC-I unrestricted natural killer (NK) cell-mediated innate immunity and T cell-mediated adaptive immunity by leveraging antigen presentation cell (APC)-like tumor cells. Genetically engineered tumor cells featuring sufficient co-stimulating molecules are cryo-shocked and conjugated with a sonosensitizer, hematoporphyrin monomethyl ether, using click chemistry. These cells (DPNLs) exhibit characteristics of tumor and draining lymph node homing. Under ultrasound, NK cell-mediated innate immunity within the tumor microenvironment could be activated, and T cells in the tumor-draining lymph nodes (TDLNs) are stimulated through co-stimulatory molecules. In combination with programmed cell death ligand 1 (PD-L1) antibody, DPNLs extend the survival time and inhibited lung metastasis in triple-negative breast cancer (TNBC) models. This study provides an alternative approach for sonoimmunotherapy with precise sonosensitizer delivery and enhanced NK cell and T cell activation.
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Affiliation(s)
- Xindi Qian
- Department of Medical Ultrasound and Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, School of Medicine, Tongji University, Shanghai, 200072, China
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Department of Ultrasound, Zhongshan Hospital, Institute of Ultrasound in Medicine and Engineering, Fudan University, Shanghai, 200032, China
| | - Wenzhe Yi
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wenlu Yan
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying Cai
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations Yantai Institute of Materia Medica Shandong, Shanghai, 264000, China
| | - Shuangshuang Hu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Dan Yan
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Zhiwen Zhao
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Rongzhang Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liying Wang
- Department of Medical Ultrasound and Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Huixiong Xu
- Department of Ultrasound, Zhongshan Hospital, Institute of Ultrasound in Medicine and Engineering, Fudan University, Shanghai, 200032, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations Yantai Institute of Materia Medica Shandong, Shanghai, 264000, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264000, China
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29
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Sheykhhasan M, Ahmadieh-Yazdi A, Heidari R, Chamanara M, Akbari M, Poondla N, Yang P, Malih S, Manoochehri H, Tanzadehpanah H, Mahaki H, Fayazi Hosseini N, Dirbaziyan A, Al-Musawi S, Kalhor N. Revolutionizing cancer treatment: The power of dendritic cell-based vaccines in immunotherapy. Biomed Pharmacother 2025; 184:117858. [PMID: 39955851 DOI: 10.1016/j.biopha.2025.117858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 02/18/2025] Open
Abstract
In the modern time, cancer immunotherapies have increasingly become vital treatment options, joining long-established methods like surgery, chemotherapy, and radiotherapy treatment. Central to this emerging approach are dendritic cells (DCs), which boast a remarkable ability for antigen presentation. This ability is being leveraged to modulate T and B cell immunity, offering a groundbreaking strategy for tackling cancer. However, the percentage of patients experiencing meaningful benefits from this treatment remains relatively low, underscoring the ongoing necessity for further research and development in this field. This review offers a comprehensive analysis of the present-day progress in dendritic cell (DC)-based vaccines and recent efforts to enhance their efficacy. We explore the intricacies of DC function, from antigen capture to T cell stimulation, and discuss the outcomes of both preclinical and clinical trials across various cancer types. While the results are promising, the real-world application of DC-based vaccines is still nascent, posing multiple challenges that need to be overcome. These obstacles include optimizing the methods for DC generation and antigen loading, overcoming the immunosuppressive nature of the tumor microenvironment, and enhancing specificities of the immunologic response through personalized vaccines. The review concludes by emphasizing prospective opportunities for future research and emphasizing the critical need for extensive clinical trials. These trials are essential to validate the effectivity of DC-based vaccines and solidify their role in the broader spectrum of cancer immunotherapy options.
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Affiliation(s)
- Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
| | - Amirhossein Ahmadieh-Yazdi
- Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Reza Heidari
- Infectious Diseases Research Center, AJA University of Medical Sciences, Tehran, Iran; Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran; Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Mohsen Chamanara
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran; Student research committee, AJA University of Medical Sciences, Tehran, Iran
| | - Mohammad Akbari
- Department of Medical School, Faculty of Medical Sciences, Islamic Azad University, Tonekabon Branch, Mazandaran, Iran
| | - Naresh Poondla
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Global Health Research, Saveetha Medical College & Hospital, Chennai, India
| | - Piao Yang
- Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210, USA
| | - Sara Malih
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA; Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Basic Science Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nashmin Fayazi Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ashkan Dirbaziyan
- Department of Microbiology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | | | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran
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30
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Cui X, Song Y, Han J, Yuan Z. The multifaceted role of SMAD4 in immune cell function. Biochem Biophys Rep 2025; 41:101902. [PMID: 39802394 PMCID: PMC11721226 DOI: 10.1016/j.bbrep.2024.101902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.
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Affiliation(s)
- Xinmu Cui
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Yu Song
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Jianfeng Han
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
- Cellular Biomedicine Group Inc, Shanghai, 201203, China
| | - Zhaoxin Yuan
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
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31
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Wang Y, Liu C, Pang J, Li Z, Zhang J, Dong L. The Extra-Tumoral Vaccine Effects of Apoptotic Bodies in the Advancement of Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2410503. [PMID: 39871756 PMCID: PMC11878267 DOI: 10.1002/smll.202410503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.
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Affiliation(s)
- Yulian Wang
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
| | - Chunyan Liu
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
| | - Jiayun Pang
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
| | - Zhenjiang Li
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
| | - Lei Dong
- State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsu210023China
- Chemistry and Biomedicine Innovative CenterNanjing UniversityNanjingJiangsu210023China
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32
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Zhao C, Jia B, Jiang Y, Shike H, Annageldiyev C, Cioccio J, Minagawa K, Mineishi S, Ehmann WC, Schell TD, Cheng H, Zheng H. Cytotoxic lymphocytes induced by engineered human dendritic cells mediate potent anti-leukemia activity. Cancer Immunol Immunother 2025; 74:117. [PMID: 39998689 PMCID: PMC11861774 DOI: 10.1007/s00262-025-03971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 02/06/2025] [Indexed: 02/27/2025]
Abstract
Effective treatment of acute myeloid leukemia (AML) remains an urgent unmet need. Adoptive transfer of cytotoxic T cells (CTLs) against leukemia-associated antigen (LAA) has strong potential to improve AML treatment. However, the clinical translation of this therapeutic modality is hindered by the difficulty of obtaining large quantities of LAA-specific CTLs. Stimulating naïve T cells using monocyte-derived dendritic cells (MoDCs) loaded with LAA is commonly used for the generation of CTLs. This approach has drawbacks as MoDCs loaded with desired antigen need to be developed repeatedly with multiple steps and have limited growth potential. We have established immortalized human dendritic cells (DC) lines (termed ihv-DCs). Here, we report the successful generation of CTLs by culturing AML patient-derived T cells with our off-the-shelf ihv-DCs that carry HLA-A2-restricted human telomerase reverse transcriptase (hTERT), a known LAA. These CTLs exert a potent cytotoxic activity against leukemia cell lines and primary AML blasts in vitro. Importantly, using a highly clinically relevant PDX model where CTLs (derived from clinical donors) were adoptively transferred into NSG mice bearing patient-derived AML cells (that were partial or full HLA match with the donors), we showed that the CTLs effectively reduced leukemia growth in vivo. Our results are highly translational and provide proof of concept using the novel DC methodology to improve the strategy of adoptive T cell transfer for AML treatment.
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MESH Headings
- Humans
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Dendritic Cells/transplantation
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/transplantation
- Animals
- Mice
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/therapy
- Immunotherapy, Adoptive/methods
- Telomerase/immunology
- Telomerase/genetics
- Telomerase/metabolism
- Mice, Inbred NOD
- Cytotoxicity, Immunologic
- Mice, SCID
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- HLA-A2 Antigen/immunology
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Affiliation(s)
- Chenchen Zhao
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Bei Jia
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Yixing Jiang
- Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201, USA
| | - Hiroko Shike
- Department of Pathology, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Charyguly Annageldiyev
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Joseph Cioccio
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Kentaro Minagawa
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Shin Mineishi
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - WChristopher Ehmann
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Todd D Schell
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, 17033, USA
| | - Hua Cheng
- ImmuCision Biotherapeutics, LLC, 801W Baltimore Street, Baltimore, MD, 21201, USA
| | - Hong Zheng
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, 17033, USA.
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Cai P, Sun H, Jiang T, Li H, Huang D, Hao X, Wang W, Xing W, Liang G. Harnessing TAGAP to improve immunotherapy for lung squamous carcinoma treatment by targeting c-Rel in CD4+ T cells. Cancer Immunol Immunother 2025; 74:114. [PMID: 39998561 PMCID: PMC11861500 DOI: 10.1007/s00262-025-03960-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/27/2025] [Indexed: 02/27/2025]
Abstract
Revealing the immunosenescence, particularly in CD4+ T cell function in lung squamous carcinoma (LUSC) assists in devising individual treatment strategies. This study identifies differentially expressed genes (DEGs) between ROS1 mutated (ROS1MUT) and wild-type (ROS1WT) LUSC samples from the TCGA database. Using WGCNA, immune-related DEGs (IRGs) were screened. Prognostic signatures derived from IRGs were used to compare immune infiltration, chemotherapy sensitivity, and immune-phenotyping score (IPS) between high- and low-risk subgroups. Hub gene abundance in different cell clusters was analyzed via Sc-seq. TAGAP overexpression or silencing was employed to assess its impact on cytokines production and differentiation of CD4+ T cells, downstream c-Rel expression, and tumor progression. High-risk subgroups exhibited decreased infiltration of natural killer, follicular helper T, and CD8+ T cells, but increased plasma, CD4+ memory resting T, and macrophage M2 cells. These subgroups were more sensitive to Sunitinib and CTLA4 blockade. TAGAP expression was significantly reduced in LUSC. Overexpressing TAGAP enhanced CD4+ T cells to produce cytokines, promoted differentiation into Th1/Th17 cells, inhibited Treg conversion, and suppressed LUSC cell phenotype in vitro. TAGAP overexpression in CD4+ T cells also inhibited LUSC tumor growth and boosted immune infiltration in vivo. TAGAP's effects on CD4+ T cells were partly reversed by c-Rel overexpression, highlighting TAGAP's role in rejuvenating CD4+ T cells and exerting anticancer effects by inhibiting c-Rel. This study elucidates the novel therapeutic potential of targeting TAGAP to modulate CD4+ T cell activity in immunotherapy for LUSC.
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Affiliation(s)
- Peian Cai
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Haibo Sun
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Tongmeng Jiang
- Key Laboratory of Emergency and Trauma, Ministry of Education, Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, College of Emergency and Trauma, Hainan Provincial Stem Cell Research Institute, Hainan Medical University, Haikou, 571199, China.
| | - Huawei Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Dejing Huang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xiaopei Hao
- Department of Hepatobiliary Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wei Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wenqun Xing
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Guanghui Liang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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34
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Xia W, Feng Z, Wang Y, Lei R, Zhou Y, Zhuo Y, Xie R, Dong H, Zhao X, Guan X, Wu J. Orthogonally Engineered Bacteria Capture Metabolically Labeled Tumor Antigens to Improve the Systemic Immune Response in Irradiated Tumors. ACS NANO 2025; 19:5376-5391. [PMID: 39889238 DOI: 10.1021/acsnano.4c13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2025]
Abstract
In situ vaccination is considered a promising cancer immunotherapy strategy to elicit a tumor-specific T cell response. Live bacteria effectively enhanced the immune response in irradiated tumors as it can activate multiple immune cells. However, the adaptive immune response remains low since bacteria lack the efficient delivery of antigen to dendritic cells (DCs). Here, we show that tumor antigens can be metabolically labeled with azido groups in situ, allowing for their specific capture by orthogonally engineered Salmonella via bioorthogonal chemistry. Subsequently, these antigens are efficiently delivered to DCs through the active movement of the bacteria. Intratumorally injected engineered bacteria captured the labeled antigens and improved their presentation by DCs. This increased the proportion of antigen-specific CD8+ T cells in tumors, further resulting in systemic antitumor effects in the bilateral melanoma mouse model. The antitumor effects were abrogated in Batf3-/- mice or after CD8+ T cell depletion, indicating that systemic antitumor effects were dependent on adaptive immune responses. Overall, our work presents a strategy combining bacterial engineering and antigen labeling, which may guide the development of in situ vaccines in the future.
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Affiliation(s)
- Wen Xia
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
- Department of Andrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Gulou District, Nanjing 210008, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
- Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China
- Institute of Drug Research and Development & Jiangsu Engineering Center of Biointelligent Materials, Nanjing University, Nanjing 210093, China
- Wuxi Xishan NJU Institute of Applied Biotechnology, Anzhen Street, Xishan District, Wuxi 214101, China
| | - Zhuo Feng
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
| | - Yuchen Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
| | - Ruiqi Lei
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
| | - Yao Zhou
- Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China
| | - Yujia Zhuo
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
| | - Ran Xie
- Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China
| | - Hong Dong
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
| | - Xiaozhi Zhao
- Department of Andrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Gulou District, Nanjing 210008, China
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, China
- Department of Andrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Gulou District, Nanjing 210008, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
- Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China
- Institute of Drug Research and Development & Jiangsu Engineering Center of Biointelligent Materials, Nanjing University, Nanjing 210093, China
- Wuxi Xishan NJU Institute of Applied Biotechnology, Anzhen Street, Xishan District, Wuxi 214101, China
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Li X, Qian Y, Lu X, Xu M, He S, Zhang J, Song S. Iodine-131 radioembolization boosts the immune activation enhanced by icaritin/resiquimod in hepatocellular carcinoma. J Control Release 2025; 378:849-863. [PMID: 39730069 DOI: 10.1016/j.jconrel.2024.12.064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 12/29/2024]
Abstract
Transarterial radioembolization (TARE) is a recommended locoregional strategy for intermediate hepatocellular carcinoma (HCC), whereas, the effect is insufficient to reverse the immunosuppression tumor microenvironment, and the overall benefits for patients remain to be improved. In this study, a multifunctional microsphere (MS) 131I-ICT/R848-MS is developed to propose an approach combined with TARE, icaritin (ICT) and immune modulator resiquimod (R848). ICT and iodine-131 (131I) radiation can induce immunogenic cell death, which, in combination with R848, will boost dendritic cell (DC) maturation. Decellularized liver model and SPECT/CT imaging revealed high specificity and long retention of microspheres. Radioactive distribution of 131I in tumor on 7 d following 131I-MS injection was over 7 times of that in normal liver tissue (4.26 ± 1.21 % ID/g vs 0.57 ± 0.23 % ID/g). 131I-ICT/R848-MS embolization brought significant immune activation, where the ratio of cytotoxic T lymphocytes to regulatory T cells in tumor sites upregulated from 1.75 ± 0.20 to 24.31 ± 1.79, and DC maturation in lymph nodes increased from 8.90 ± 1.51 % to 34.70 ± 3.12 %. Enhanced anti-tumor efficacy with no relapse was proved in rat orthotopic N1S1 HCC models. These results demonstrated the great potential of this multifunctional embolic agent to treat HCC through transarterial radio-immuno-chemoembolization (TARICE).
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Affiliation(s)
- Xinyi Li
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Yuyi Qian
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Xin Lu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Mingzhen Xu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Simin He
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Jianping Zhang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
| | - Shaoli Song
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, China.
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Liu Y, Shen S, Wang X, Chen H, Ren W, Wei H, Li K, Li L. GATA3-Driven ceRNA Network in Lung Adenocarcinoma Bone Metastasis Progression and Therapeutic Implications. Cancers (Basel) 2025; 17:559. [PMID: 39941924 PMCID: PMC11816722 DOI: 10.3390/cancers17030559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/18/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Background/Objectives: Bone metastasis is a common and severe complication of lung adenocarcinoma (LUAD), impacting prognosis and treatment outcomes. Understanding the molecular mechanisms behind LUAD bone metastasis (LUADBM) is essential for developing new therapeutic strategies. The interactions between long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in the competing endogenous RNA (ceRNA) network are crucial in cancer progression and metastasis, but the regulatory mechanisms in LUADBM remain unclear. Methods: Microarray analysis was performed on clinical samples, followed by weighted gene co-expression network analysis (WGCNA) and construction of a ceRNA network. Molecular mechanisms were validated using colony formation assays, transwell migration assays, wound healing assays to assess cell migration, and osteoclastogenesis assays to evaluate osteoclast differentiation. Potential therapeutic drugs and their binding affinities were predicted using the CMap database and Kdeep. The interaction between the small-molecule drug and its target protein was confirmed by surface plasmon resonance (SPR) and drug affinity responsive target stability (DARTS) assays. Mechanistic insights and therapeutic efficacy were further validated using patient-derived organoid (PDO) cultures, drug sensitivity assays, and in vivo drug treatments. Results: Our results identified the XLOC_006941/hsa-miR-543/NPRL3 axis as a key regulatory pathway in LUADBM. We also demonstrated that GATA3-driven Th2 cell infiltration creates an immunosuppressive microenvironment that promotes metastasis. Additionally, we confirmed that the inhibitor E7449 effectively targets NPRL3, and its combination with the IL4R-blocking antibody dupilumab resulted in improved therapeutic outcomes in LUADBM. Conclusions: These findings offer new insights into the molecular mechanisms of LUADBM and highlight potential therapeutic targets, including the XLOC_006941/miR-543/NPRL3 axis and GATA3-driven Th2 cell infiltration. The dual-target therapy combining E7449 with dupilumab shows promise for improving patient outcomes in LUADBM, warranting further clinical evaluation.
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Affiliation(s)
- Yun Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China
| | - Shihui Shen
- Joint Center for Translational Medicine, Shanghai Fifth People’s Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai 200240, China
- School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xudong Wang
- Department of Orthopedic Oncology, Changzheng Hospital, Shanghai 200003, China
- Department of Orthopedics, 905th Hospital of PLA Navy, Shanghai 200030, China
| | - Hansen Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China
| | - Wenjie Ren
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China
| | - Haifeng Wei
- Department of Orthopedic Oncology, Changzheng Hospital, Shanghai 200003, China
- Department of Orthopedics, 905th Hospital of PLA Navy, Shanghai 200030, China
| | - Kun Li
- Health Science Center, East China Normal University, Shanghai 200241, China
| | - Lei Li
- Joint Center for Translational Medicine, Shanghai Fifth People’s Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai 200240, China
- School of Life Sciences, East China Normal University, Shanghai 200241, China
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37
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Ezzatizadeh F, Bolhassani A, Nematalahi FS, Fateh A. Immunotherapeutic effects of TCL-E5 and TCL-E5-pulsed DCs: two novel HPV therapeutic vaccine candidates. Immunotherapy 2025; 17:191-199. [PMID: 40099844 PMCID: PMC11951720 DOI: 10.1080/1750743x.2025.2478814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
AIM This study investigated the potential of HPV16 E5 oncoprotein-modified tumor cell lysate (TCL-E5) and dendritic cells (DCs) pulsed with TCL-E5 (TCL-E5-pulsed DCs) to enhance antitumor immunity in a murine model. MATERIALS AND METHODS For generation of TCL-E5, TC1 tumor cells were transduced with lentiviral particles harboring E5 protein. Moreover, the cell supernatants were prepared from DCs pulsed with TCL-E5. Their immunological responses and antitumor effects were investigated in a mouse model. RESULTS The TCL-E5-pulsed DCs regimen could direct immunity toward Th1 and CTL responses, leading to tumor volume reduction and high percentage of tumor-free mice. CONCLUSION The TCL-pulsed DCs regimen could not induce significant antitumor effects compared to TCL-E5-pulsed-DCs regimen indicating main role of E5 in vaccine development.
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Affiliation(s)
- Fahimeh Ezzatizadeh
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis, AIDS and Blood-Borne Diseases, Pasteur Institute of Iran, Tehran, Iran
| | | | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
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38
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Hou H, Liu X, Liu J, Wang Y. Carbohydrate polymer-based nanoparticles with cell membrane camouflage for cancer therapy: A review. Int J Biol Macromol 2025; 289:138620. [PMID: 39674458 DOI: 10.1016/j.ijbiomac.2024.138620] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/21/2024] [Accepted: 12/08/2024] [Indexed: 12/16/2024]
Abstract
Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.
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Affiliation(s)
- Haijia Hou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuejian Liu
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun Liu
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yudong Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
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Yalamandala BN, Moorthy T, Liu ZH, Huynh TMH, Iao HM, Pan WC, Wang KL, Chiang CS, Chiang WH, Liao LD, Liu YC, Hu SH. A Self-Cascading Catalytic Therapy and Antigen Capture Scaffold-Mediated T Cells Augments for Postoperative Brain Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406178. [PMID: 39676476 DOI: 10.1002/smll.202406178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/19/2024] [Indexed: 12/17/2024]
Abstract
The recruitment of T lymphocytes holds great potential for suppressing the most aggressive glioblastoma (GBM) recurrence with immunotherapy. However, the phenomenon of immune privilege and the generally low immunogenicity of vaccines often reduce the presence of lymphocytes within brain tumors, especially in brain tumor recurrence clusters. In this study, an implantable self-cascading catalytic therapy and antigen capture scaffold (CAS) that can boost catalytic therapy efficiency at post-surgery brain tumor and capture the antigens via urethane-polyethylene glycol-polypropylene glycol (PU-EO-PO) segments are developed for postoperative brain immunotherapy. The CAS consists of 3D-printed elastomers modified with iron (Fe2+) metal-organic frameworks (MOFs, MIL88) and acts as a programmed peroxide mimic in cancer cells to initiate the Fenton reaction and sustain ROS production. With the assistance of chloroquine (CQ), autophagy is inhibited through lysosome deacidification, which interrupts the self-defense mechanism, further enhances cytotoxicity, and releases antigens. Then, CAS containing PU-EO-PO groups acts as an antigen depot to detain autologous tumor-associated antigens to dendritic cells maturation and T cell augments for sustained immune stimulation. CAS enhanced the immune response to postoperative brain tumors and improved survival through brain immunotherapy.
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Affiliation(s)
- Bhanu Nirosha Yalamandala
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Thrinayan Moorthy
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Zhuo-Hao Liu
- Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan
- Chang Gung University School of Medicine, Taoyuan, 33305, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Thi My Hue Huynh
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Hoi Man Iao
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Wan-Chi Pan
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Kang-Li Wang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Chi-Shiun Chiang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
| | - Wen-Hsuan Chiang
- Department of Chemical Engineering, National Chung Hsing University, Taichung, 402, Taiwan
| | - Lun-De Liao
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, 35053, Taiwan
| | - Yu-Chen Liu
- Laboratory for Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, 565-0871, Japan
| | - Shang-Hsiu Hu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300044, Taiwan
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40
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Liu D, Liu L, Che X, Wu G. Discovery of paradoxical genes: reevaluating the prognostic impact of overexpressed genes in cancer. Front Cell Dev Biol 2025; 13:1525345. [PMID: 39911323 PMCID: PMC11794808 DOI: 10.3389/fcell.2025.1525345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/07/2025] [Indexed: 02/07/2025] Open
Abstract
Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.
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Affiliation(s)
| | | | - Xiangyu Che
- *Correspondence: Guangzhen Wu, ; Xiangyu Che,
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41
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Hong K, Cao J, Jiang W, Deng W, Huang G, Huang T, Fang J, Wang Y. A nanodrug provokes antitumor immune responses via synchronous multicellular regulation for enhanced cancer immunotherapy. J Colloid Interface Sci 2025; 678:750-762. [PMID: 39265345 DOI: 10.1016/j.jcis.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/02/2024] [Accepted: 09/02/2024] [Indexed: 09/14/2024]
Abstract
Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.
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Affiliation(s)
- Keze Hong
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
| | - Jianrong Cao
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
| | - Weiting Jiang
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
| | - Wei Deng
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
| | - Guohong Huang
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
| | - Tao Huang
- Department of Minimally Invasive Interventional Radiology, and Laboratory of Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
| | - Jin Fang
- Department of Radiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Yong Wang
- College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China.
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Wu S, Cao Z, Lu R, Zhang Z, Sethi G, You Y. Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy. Cytokine Growth Factor Rev 2025:S1359-6101(25)00001-2. [PMID: 39828476 DOI: 10.1016/j.cytogfr.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.
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Affiliation(s)
- Songsong Wu
- Department of Radiation Oncology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhumin Cao
- Department of Interventional and Vascular Surgery, The Seventh People's Hospital of Chongqing, Chongqing, China
| | - Rongying Lu
- Samueli School of Engineering, University of California, Irvine, CA, USA
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei Province 437100, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Yulai You
- Department of Hepatobiliary surgery, Chongqing University Affiliated Jiangjin Central Hospital, Chongqing, China.
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Wang H, Zhan Y, Luo J, Wang W, Fan S. Unveiling immune resistance mechanisms in nasopharyngeal carcinoma and emerging targets for antitumor immune response: tertiary lymphoid structures. J Transl Med 2025; 23:38. [PMID: 39789621 PMCID: PMC11721552 DOI: 10.1186/s12967-024-05880-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 11/13/2024] [Indexed: 01/12/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in China, commonly associated with undifferentiated cell types and Epstein-Barr virus (EBV) infection. The presence of intense lymphocytic infiltration and elevated expression of programmed cell death ligand 1(PD-L1) in NPC highlights its potential for immunotherapy, yet current treatment outcomes remain suboptimal. In this review, we explore the tumor microenvironment of NPC to better understand the mechanisms of resistance to immunotherapy, evaluate current therapeutic strategies, and pinpoint emerging targets, such as tertiary lymphoid structures (TLSs), that could enhance treatment outcomes and prognostic accuracy. TLSs have demonstrated positive prognostic value in NPC, making them a promising target for future therapies. This review summarizes the key characteristics of TLSs and latest research in the context of NPC. We are optimistic that targeting TLSs could improve immunotherapy outcomes for NPC patients, ultimately leading to more effective treatment strategies and better patient survival.
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Affiliation(s)
- Huilin Wang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Yuting Zhan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Jiadi Luo
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Weiyuan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China.
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Hosseini SA, Nasab NK, Kargozar S, Wang AZ. Advanced biomaterials and scaffolds for cancer immunotherapy. BIOMATERIALS FOR PRECISION CANCER MEDICINE 2025:377-424. [DOI: 10.1016/b978-0-323-85661-4.00016-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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45
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Liu Y, Li H, Hao YY, Huang LL, Li X, Zou J, Zhang SY, Yang XY, Chen HF, Guo YX, Guan YY, Zhang ZY. Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406870. [PMID: 39390849 DOI: 10.1002/smll.202406870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/23/2024] [Indexed: 10/12/2024]
Abstract
The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.
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Affiliation(s)
- Yang Liu
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hui Li
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yan-Yun Hao
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Ling-Ling Huang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xia Li
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jing Zou
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shi-Ying Zhang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xiao-Yue Yang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hong-Fei Chen
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yi-Xuan Guo
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yun-Yan Guan
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Zhi-Yue Zhang
- NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
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Guo Y, Wang Z, Li G, Zhan M, Xiao T, Wang J, van Hest JC, Shi X, Shen M. A polymer nanogel-based therapeutic nanovaccine for prophylaxis and direct treatment of tumors via a full-cycle immunomodulation. Bioact Mater 2025; 43:129-144. [PMID: 39386218 PMCID: PMC11462154 DOI: 10.1016/j.bioactmat.2024.09.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/15/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024] Open
Abstract
Construction of a cancer nanovaccine that can simultaneously activate immune cells and exert efficient tumor treatment still remains a challenge. Herein, we showcase a proof-of-concept demonstration of an advanced therapeutic nanovaccine formulation based on poly(N-vinylcaprolactam) nanogels (NGs) which were loaded with manganese dioxide (MnO2), the sonosensitizer chlorin e6 (Ce6), and the immune adjuvant cyclic GMP-AMP (cGAMP). The gels were furthermore coated with apoptotic cancer cell membranes (AM). On the one hand, the AM promoted the recognition of NGs by antigen presenting cells (APCs) in lymph nodes due to their enhanced immunogenicity, then the loaded Mn and cGAMP could mature APCs via stimulator of interferon genes (STING) activation for triggering immunity to prevent tumor growth. On the other hand, the NGs could selectively release Mn2+ for hydroxyl radical production and Ce6 to generate single oxygen under ultrasound irradiation of tumors, respectively, thereby exerting local chemodynamic/sonodynamic therapy to induce immunogenic cell death (ICD). Moreover, the Mn2+ could also activate STING in tumors to synergize with ICD for potentiated immune responses. Overall, the biomimetic NG-based therapeutic nanovaccine could directly evoke immune system, and also conduct local tumor treatment to further activate ICD, thus realizing a full-cycle immunomodulation (tumor killing for ICD/antigen production, and tumor cells/APCs immune activation) to tackle bilateral tumor growth.
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Affiliation(s)
- Yunqi Guo
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
| | - Zhiqiang Wang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
| | - Gaoming Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
| | - Mengsi Zhan
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
| | - Tingting Xiao
- Institute of Frontier Medical Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, PR China
| | - Jianhong Wang
- Bio-Organic Chemistry, Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600, MB, the Netherlands
| | - Jan C.M. van Hest
- Bio-Organic Chemistry, Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600, MB, the Netherlands
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
| | - Mingwu Shen
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, PR China
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47
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Cheng S, Long X, Zhang Y, Lan X, Jiang D. Advancing Cancer Vaccines with Radionuclide Imaging. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406950. [PMID: 39530610 DOI: 10.1002/smll.202406950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 10/27/2024] [Indexed: 11/16/2024]
Abstract
Cancer vaccines are emerged as a beacon of hope in the fight against cancer. However, the lack of effective methods to directly observe their in vivo behavior and monitor therapeutic responses hinders their translation into clinical settings. Radionuclide imaging allows for non-invasive and real-time visualization of vaccine biodistribution and immunological response, offering valuable insights into the effectiveness of cancer vaccines and aiding in patient stratification. In this review, the latest advances and potential applications of radionuclide imaging in cancer vaccines are discussed, with a specific focus on strategies for visualizing the spatiotemporal distribution of vaccines in vivo and monitoring treatment efficacy. The challenges and considerations for implementing these techniques in clinical practice are also highlighted, aiming to inform and guide future research in this field.
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Affiliation(s)
- Sixuan Cheng
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xingru Long
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yongxue Zhang
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiaoli Lan
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
| | - Dawei Jiang
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
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48
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Jia F, Wang W, Tian Y, Zahra A, He Y, Ge C, Zhang T, Wang M, Gong J, Zhang G, Yang G, Yang W, Shi C, Wang J, Huang H, Cao X, Zeng Y, Wang N, Wang Z, Wang C, Jiang Y. Delivery of dendritic cells targeting 3M2e-HA2 nanoparticles with a CpG adjuvant via lysosomal escape of Salmonella enhances protection against H9N2 avian influenza virus. Poult Sci 2025; 104:104616. [PMID: 39631272 PMCID: PMC11665339 DOI: 10.1016/j.psj.2024.104616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 11/30/2024] [Indexed: 12/07/2024] Open
Abstract
Avian influenza virus (AIV) subtype H9N2 still poses a great threat to the poultry farming industry and public health worldwide, and the development of a new influenza vaccine that is safe and conservative and able to address influenza virus mutations is highly promising for application. HA2, the neck of the HA protein, and M2e, the extracellular N-terminal structural domain of the M2 protein, are conserved and effective protective antigens. In this study, the HA2 sequences were fused with three M2e copies (H9N2, H1N1 and H5N1) to the norovirus VP1 protein via the SpyTag-SpyCatcher platform to form self-assembled nanoparticles and display antigenic proteins on its surface, yielding pYL262. The chicken dendritic cells (DCs) targeting the nanobody phage-54 were then fused to HA2-3M2e to yield pYL327. Finally, a synthesized 20-repeat CpG adjuvant gene fragment was inserted into pYL327, resulting in the plasmid pYL331. All the constructed plasmids were then transformed into the sifA gene-deficient Salmonella vector χYL56 for oral immunization. The results showed that sifA-deficient Salmonella could efficiently increase antigen-specific mucosal sIgA antibody titers, especially in alveolar lavage samples, whereas the presence of the phage-54 nanobody could dramatically increase intracellular IFN-γ mRNA levels, indicating its ability to enhance the Th1-type immune response. Finally, the presence of the CpG adjuvant clearly increased T-cell proliferation and promoted DC activation, with elevated splenic TLR21 levels observed. Strikingly, after oral immunization with χYL56 (pYL331), chickens were protected against challenge with the G57 genotype H9N2 virus, which presented similar or even better levels of virus shedding and body weight gain compared with the commercial inactivated vaccine, providing a new option for controlling H9N2 virus infection in the future.
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Affiliation(s)
- Futing Jia
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Wenfeng Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Yawen Tian
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Ainul Zahra
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Yingkai He
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Chongbo Ge
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Tongyu Zhang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Mingyue Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Jingshuo Gong
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Gerui Zhang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Guilian Yang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Wentao Yang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Chunwei Shi
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Jianzhong Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Haibin Huang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Xin Cao
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Yang Zeng
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Nan Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China
| | - Zhannan Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China.
| | - Chunfeng Wang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China.
| | - Yanlong Jiang
- College of Animal Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, 130118, China.
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Wang XY, Yan Y, Guo XR, Lu A, Jiang LX, Zhu YJ, Shi YJ, Liu XY, Wang JC. Enhanced Tumor Immunotherapy by Triple Amplification Effects of Nanomedicine on the STING Signaling Pathway in Dendritic Cells. Adv Healthc Mater 2025; 14:e2403143. [PMID: 39440648 DOI: 10.1002/adhm.202403143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/02/2024] [Indexed: 10/25/2024]
Abstract
Insufficient activation of stimulator of interferon genes (STING) signaling pathway in tumor-associated dendritic cells limits the efficiency of tumor immunotherapy. Herein, the "three-in-one" IAHA-LaP/siPTPN6 NPs containing lanthanum ions (La3+), cGAMP, and PTPN6 siRNA are developed for triple amplification of the STING pathway. In vitro results demonstrate that La3+ significantly promotes cGAMP-mediated activation of the STING pathway by enhancing the phosphorylation of STING, TBK1, IRF3, and NF-κB p65. Moreover, the IAHA-LaP/siPTPN6 NPs further significantly enhance the phosphorylation of STING and NF-κB p65 and augment K63-linked ubiquitination of STING protein via siPTPN6-mediated downregulation of SHP-1 protein. Furthermore, NPs improve the secretion of IFNβ (2.4-fold), IL-6 (1.5-fold), and TNF-α (1.4-fold), thereby promoting DCs maturation compared to the mixture of La3+ and cGAMP. In vivo results show that the IAHA-LaP/siPTPN6 NPs remarkably inhibit primary tumor growth by increasing the percentage of mature DCs in tumor-draining lymph nodes, polarizing M2/M1 phenotype in TME, and promoting the infiltration of CD8+T cells into tumors. Moreover, these NPs dramatically prevent the growth of distal tumor by inducing systemic anti-tumor immunity and generating a long-term anti-tumor memory for protection against tumor recurrence in mice bearing bilateral B16F10. These IAHA-LaP/siPTPN6 NPs may offer a promising platform for robust anti-tumor immune responses.
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Affiliation(s)
- Xiang-Yu Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yi Yan
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiao-Ru Guo
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - An Lu
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Lin-Xia Jiang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuan-Jun Zhu
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yu-Jie Shi
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiao-Yan Liu
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jian-Cheng Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Laboratory of Innovative Formulations and Pharmaceutical Excipients, Peking University Ningbo Institute of Marine Medicine, Ningbo, 315832, China
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50
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Long Z, Wu Y, Zhong L, Lu J, Liu B. Bibliometric analysis of dendritic cell-based vaccines over the past 15 years. Hum Vaccin Immunother 2024; 20:2392961. [PMID: 39161160 PMCID: PMC11340764 DOI: 10.1080/21645515.2024.2392961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/17/2024] [Accepted: 08/12/2024] [Indexed: 08/21/2024] Open
Abstract
Dendritic cells, which are crucial for inducing T-cell responses, are pivotal in current immunotherapy strategies aiming to replenish depleted T cells within the tumor microenvironment to combat tumors. Consequently, dendritic cell vaccine-based cancer therapies have garnered significant attention. Through bibliometric analysis, we examined research trends in this field. We searched the Web of Science core database and identified 16,476 articles on dendritic cell-based vaccines published from January 1, 2009, to December 30, 2023. The United States leads in this research domain, with Emory University being a prominent collaborator. The Journal of Immunology is the primary publication outlet, and Banchereau, J emerges as the most influential author. Recent hot keywords include nanoparticle, delivery, cancer vaccine, and clinical trial, indicating that cancer immunotherapy research, especially dendritic cell-based vaccines, is poised to become a future trend and hotspot.
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Affiliation(s)
- Zhi Long
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi, China
- Hypothalamic-Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yinghua Wu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi, China
- Hypothalamic-Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Liangchen Zhong
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi, China
| | - Jiping Lu
- Orthopedics Department, 921 Hospital, Joint Logistics Support Force People’s Liberation Army of China, Changsha, China
| | - Bo Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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