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Yan Y, Kong X, Jin X, Bu J, Ni B, Rao Z, Guo J, Xu S. RNA‑binding protein MBNL1 regulates tumor growth, chemosensitivity and antitumor immunity in lung adenocarcinoma by controlling the expression of tumor suppressor RNF125. Oncol Rep 2025; 54:74. [PMID: 40341413 PMCID: PMC12075997 DOI: 10.3892/or.2025.8907] [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: 10/23/2024] [Accepted: 04/01/2025] [Indexed: 05/10/2025] Open
Abstract
Ring finger protein 125 (RNF125), a ubiquitin E3 ligase, has been reported to act as a tumor suppressor in several cancers, but its precise function in lung adenocarcinoma (LUAD) has not been elucidated. In the present study, through bioinformatics analysis and immunohistochemistry in LUAD and non‑cancerous samples, it was demonstrated that RNF125 was significantly downregulated in lung cancer. Low levels of RNF125 expression were associated with metastatic status, advanced tumor stage and poor overall survival in LUAD. The results of gain‑ and loss‑of‑function experiments demonstrated that RNF125 inhibited proliferation, colony formation, migration and invasion of LUAD cells. In addition, RNF125 increased the sensitivity of LUAD cells to cisplatin. Mechanistically, RNF125 interacted with programmed cell death ligand 1 (PD‑L1) and reduced PD‑L1 expression levels in LUAD cells. Furthermore, IL‑2 secretion by Jurkat T cells was significantly suppressed when co‑cultured with RNF125‑silenced LUAD cells. NK‑92 cell lysis of RNF125‑silenced LUAD cells was also weaker compared with that of control LUAD cells, suggesting that RNF125 knockdown enhanced the immune evasion ability of LUAD cells. Notably, the results of the present study identified that the RNA‑binding protein muscleblind‑like 1 (MBNL1) is the upstream regulator of RNF125 in LUAD. MBNL1 increased the stability of the RNF125 transcript in LUAD cells and knockdown of RNF125 reversed the antitumor effect of MBNL1 on LUAD cells. In conclusion, the present study demonstrated the tumor suppressor role of RNF125 in LUAD and implicated MBNL1 as an upstream regulator of RNF125 in LUAD. These findings contributed to an improved understanding of the molecular features of LUAD progression.
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Affiliation(s)
- Yubo Yan
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Xianglong Kong
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Xiangyuan Jin
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Jianlong Bu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Boxiong Ni
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Zuqin Rao
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Junnan Guo
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Shidong Xu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
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2
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Xu L, Li K, Li J, Xu F, Liang S, Kong Y, Chen B. The crosstalk between lung adenocarcinoma cells and M2 macrophages promotes cancer cell development via the SFRS1/miR-708-5p/PD-L1 axis. Life Sci 2025; 371:123599. [PMID: 40185466 DOI: 10.1016/j.lfs.2025.123599] [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: 01/07/2025] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
This study aimed to elucidate the underlying mechanisms regarding microRNA-708-5p (miR-708-5p) in lung adenocarcinoma (LUAD). Here, the co-culture system of LUAD cells and macrophages, as well as a xenograft mouse model, were established. High levels of miR-708-5p were observed in LUAD. Exosomal miR-708-5p facilitated M2-like phenotype polarization, whereas miR-708-5p inhibition blocked the polarization. Exosomal miR-708-5p was identified as a pivotal signaling molecule for macrophages to mediate tumor cell proliferation, invasion, migration and IFN-γ production in T cells. In addition, miR708-5p was observed to induce PD-L1 expression, and PD-L1 silencing inhibited macrophage-induced tumor cell growth behavior and regulated CD8 T cell activity. In xenograft models, miR-708-5p inhibition and PD-L1 silencing attenuated macrophage-induced tumor growth, induced IFN-γ secretion and CD8 expression, and modulated the PTEN/AKT/mTOR pathway. In LUAD patients, there was an upregulation of both miR-708-5p and PD-L1 expression, accompanied by the activation of PTEN/AKT/mTOR. In conclusion, this study demonstrated the induction of M2 macrophage polarization and PD-L1 expression by exosomal miR-708-5p. We observed that exosomal miR-708-5p mediated the PTEN/AKT/mTOR pathway, diminished CD8 T cell activity and accelerated LUAD progression. The inhibition of specific exosomal miRNA secretion and anti-PD-L1 in the LUAD microenvironment may represent a promising avenue for LUAD immunotherapy.
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Affiliation(s)
- Li Xu
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China
| | - Kang Li
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China
| | - Jia Li
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China
| | - Fang Xu
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China
| | - Shuzhi Liang
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China
| | - Yi Kong
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China.
| | - Bolin Chen
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China.
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3
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Wang Y, Tang C, Wang K, Zhang X, Zhang L, Xiao X, Lin H, Xiong L. The role of ferroptosis in breast cancer: Tumor progression, immune microenvironment interactions and therapeutic interventions. Eur J Pharmacol 2025; 996:177561. [PMID: 40154567 DOI: 10.1016/j.ejphar.2025.177561] [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: 12/29/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.
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Affiliation(s)
- Yi Wang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Chuanyun Tang
- First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Keqin Wang
- First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Xiaoan Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Lifang Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xinghua Xiao
- Department of Pathology, The First Affiliated Hospital, Nanchang University, 17 Yongwaizheng Road, Nanschang, 330066, China
| | - Hui Lin
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Lixia Xiong
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
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4
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Lazo PA. VRK2 kinase pathogenic pathways in cancer and neurological diseases. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119949. [PMID: 40187568 DOI: 10.1016/j.bbamcr.2025.119949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/07/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
The VRK2 ser-thr kinase, belonging to the dark kinome, is implicated in the pathogenesis of cancer progression, neurological and psychiatric diseases. The VRK2 gene codes for two isoforms. The main isoform (VRK2A) is mainly located in the cytoplasm, and anchored to different types of membranes, such as the endoplasmic reticulum, mitochondria and nuclear envelope. The VRK2A isoform interacts with signaling modules assembled on scaffold proteins such as JIP1 or KSR1, forming stable complexes and blocking the activation of regulatory signaling pathways by altering their intracellular localization and the balance among them. VRK2 regulates apoptosis, nuclear membrane organization, immune responses, and Cajal bodies. Wild-type VRK2 is overexpressed in tumors and contributes to cancer development. In cells and tumors with low levels of nuclear VRK1, VRK2 generates by alternative splicing a shorter isoform (VRK2B) that lacks the C-terminal hydrophobic tail and permits its relocation to nuclei. Furthermore, rare VRK2 gene variants are associated with different neurological or psychiatric diseases such as schizophrenia, epilepsy, bipolar disorder, depression, autism, circadian clock alterations and insomnia, but their pathogenic mechanism is unknown. These diseases are a likely consequence of an altered balance among different signaling pathways that are regulated by VRK2.
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Affiliation(s)
- Pedro A Lazo
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
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5
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Zhang Z, Zhao Q, Xu Q, Deng Q, Hua A, Wang X, Yang X, Li Z. A mitochondria-interfering nanocomplex cooperates with photodynamic therapy to boost antitumor immunity. Biomaterials 2025; 317:123094. [PMID: 39799701 DOI: 10.1016/j.biomaterials.2025.123094] [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: 11/07/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.
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Affiliation(s)
- Zhijie Zhang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Qingfu Zhao
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Qingqing Xu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Qingyuan Deng
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Ao Hua
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Xing Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
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6
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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [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: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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7
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Allela OQB, Al-Hussainy AF, Sanghvi G, Roopashree R, Kashyap A, Anand DA, Panigrahi R, Garifulina LM, Taher SG, Alwan M, Jawad M, Mushtaq H. Tumor immune evasion and the Let-7 family: insights into mechanisms and therapies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04283-9. [PMID: 40423803 DOI: 10.1007/s00210-025-04283-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025]
Abstract
Tumor immune evasion is a complex and adaptive mechanism that allows cancer cells to escape immune detection and destruction, contributing to malignancy progression and poor therapeutic outcomes. This review article explores the integral role of the let-7 family of microRNAs (miRNAs) in mediating tumor immune evasion, particularly how these regulators influence the tumor microenvironment (TME) and immune cell functionality. The let-7 family, known for its tumor-suppressive roles, modulates key immune checkpoints, including PD-L1, and pathways linked to immune response regulation, such as the STAT3/SOCS axis, impacts macrophage polarization and modulates immune cell function. Dysregulation of let-7 miRNAs can enhance tumor immune evasion through mechanisms such as downregulating major histocompatibility complex (MHC) expressions, promoting immunosuppressive cell populations, and manipulating metabolic pathways, which together establish an immunosuppressive TME. Conversely, specific let-7 members show potential in restoring anti-tumor immunity by reversing immune suppression and improving T cell responses. By synthesizing current research, this article underscores the dual role of let-7 in both promoting and inhibiting tumor immune evasion, suggesting their potential as therapeutic targets and biomarkers in cancer immunotherapy. Future studies on the context-dependent roles and advanced delivery systems for let-7-targeting therapies are crucial for enhancing immunotherapeutic efficacy and improving patient outcomes across malignancies.
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Affiliation(s)
| | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - D Alex Anand
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rajashree Panigrahi
- Department of Microbiology, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751003, India
| | | | - Sada Ghalib Taher
- College of Health and Medical Technology, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | - Mariem Alwan
- Pharmacy college, Al-Farahidi University, Baghdad, Iraq
| | - Mahmood Jawad
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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8
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Sun C, Liu S, Lau JW, Yang H, Chen Y, Xing B. Enzyme-Activated Orthogonal Proteolysis Chimeras for Tumor Microenvironment-Responsive Immunomodulation. Angew Chem Int Ed Engl 2025; 64:e202423057. [PMID: 39932237 DOI: 10.1002/anie.202423057] [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: 11/26/2024] [Indexed: 02/20/2025]
Abstract
Precise modulation of dynamic and complex tumor microenvironment (TME) to disrupt tumorigenesis and reshape intratumoral immune infiltration has emerged as promising approaches for enhanced cancer therapy. Among recent innovations, proteolysis-targeting chimeras (PROTACs) represent a burgeoning chemical knockdown technology capable of degrading oncogenic protein homeostasis and inducing dynamic alternations within carcinoma settings, offering potential for antitumor manipulation. However, achieving selectivity in PROTACs that respond to disease environmental stimulation and precisely perturb on-target proteins remains challenging. The multi-step synthesis and limited permeability, attributed to high-molecular-weight and heterobifunctional structures, further hinder their in vivo efficacy. Herein, we present a unique TME-responsive enzyme-activated clickable PROTACs, which features a short peptide-tagged pomalidomide derivative to undergo tumor-specific cleavage by cathepsin protease to induce orthogonal crosslinking of the exposed cysteine with 2-cyanobenzothiazole-labeled epigenetic protein-ligand JQ1, facilitating in situ degrader formation within tumor regions only. Systematic protein profiling and proteomic analysis revealed that such TME-specific clickable-PROTACs not only selectively eliminate epigenetic proteins without tedious pre-synthesis to bridge disparate small-molecule bi-warhead fragments, but also demonstrated superior tumor penetration compared to conventional high-molecular-weight PROTACs. Importantly, these clickable-PROTACs efficiently downregulated immune checkpoint programmed death-ligand 1 (PD-L1) both in vitro and in vivo, remodeling TME for enhanced therapeutics, especially in anti-tumoral immunomodulation.
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Affiliation(s)
- Caixia Sun
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Songhan Liu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Jun Wei Lau
- Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore
| | - Hanyu Yang
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Yun Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Bengang Xing
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Rd, Hung Hom, Kowloon, Hong Kong SAR, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
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9
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Zhao J, Li Y, Zhu J, Li H, Jin X. Ubiquitination in hepatocellular carcinoma immunity. J Transl Med 2025; 23:574. [PMID: 40410880 PMCID: PMC12102898 DOI: 10.1186/s12967-025-06592-2] [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: 02/10/2025] [Accepted: 05/08/2025] [Indexed: 05/25/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide, and represents a major global health challenge. While surgical resection at early stages offers favorable prognosis with 5-year survival rates exceeding 70%, the clinical reality in China reveals a contrasting scenario, where over 60% of patients present with advanced disease, resulting in a dramatic decline in 5-year survival to below 12.5%. The immunological landscape plays a pivotal role in HCC pathogenesis and progression, comprising two complementary arms: the innate immune system's rapid-response mechanism for immediate tumor surveillance and the adaptive immune system's antigen-specific targeting with immunological memory capabilities. Emerging evidence has highlighted ubiquitination, a sophisticated post-translational modification system, as a critical regulator of immune homeostasis in HCC pathogenesis. This molecular process exerts precise control through three primary mechanisms: (1) Modulation of immune cell activation thresholds via proteasomal degradation of signaling proteins, (2) Orchestrating immune cell differentiation through stability regulation of transcriptional factors, and (3) Maintenance of immune tolerance by dynamic modification of checkpoint regulators. Such multifaceted regulation affects both innate immune recognition pathways (e.g., NF-κB and STING signaling) and adaptive immune effectors (particularly T cell receptor signaling cascades). This comprehensive review establishes a threefold Objective: First, to elucidate the mechanistic interplay between ubiquitination networks and HCC-related immune dysregulation; Second, to systematically analyze how innate immune-associated ubiquitination events drive hepatocarcinogenesis through chronic inflammation modulation; and third, to critically evaluate recent clinical advances combining ubiquitination-targeted therapies (e.g., proteasome inhibitors and E3 ligase modulators) with immunotherapeutic regimens. Our synthesis revealed that strategic manipulation of ubiquitination pathways can potentiate PD-1/PD-L1 blockade efficacy while mitigating therapeutic resistance, particularly through modulation of tumor-associated macrophages and exhausted T cell populations. By integrating fundamental mechanistic insights with translational clinical data, this review provides a conceptual framework for the development of next-generation diagnostic biomarkers and rational therapeutic combinations. The proposed strategy of ubiquitination-immune axis modulation holds significant potential to transform current HCC management paradigms, offering new avenues for precision immunotherapy for this challenging malignancy.
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Affiliation(s)
- Jianan Zhao
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Yuxuan Li
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Jie Zhu
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
| | - Hong Li
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China.
| | - Xiaofeng Jin
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China.
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10
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Zou Y, Jiang J, Li Y, Ding X, Tong Q, Shi Y, Xiao L, Chen L. Immune Checkpoint PD-L1 Modulates Retinal Microglial Activation to Alleviate Vascular Leakage in Choroidal Neovascularization via ERK. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2400747. [PMID: 40395179 DOI: 10.1002/advs.202400747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/31/2025] [Indexed: 05/22/2025]
Abstract
Neovascular age-related macular degeneration (NVAMD) is a common retinal disease causing vision loss in the elderly. Neuroinflammation significantly contributes to NVAMD's etiology. This study explores the role of Programmed cell death ligand 1 (PD-L1), an immune checkpoint (ICP) in microglia, known for limiting neuroinflammation in neurodegenerative diseases, and its potential function in NVAMD. This work finds increased PD-L1 expression in retinal microglia following laser injury. PD-L1 knockout (KO) or inhibitory PD-L1 antibody treatment worsens vascular leakage and neoangiogenesis in a laser-induced NVAMD mouse model, effects reversible by microglia depletion with PLX5622. This study underscores that choroidal neovascularization (CNV) may be regulated by multiple mechanisms, with PD-L1 modulation representing one of these pathways. Blocking PD-L1 elevated proinflammatory factors and p-ERK levels, indicating microglial overactivation in NVAMD. Conversely, enhancing PD-L1 signaling reduced neuroinflammation and neovascularization via ERK. These findings highlight PD-L1's role in neoangiogenesis and neuroinflammation in NVAMD, suggesting its potential as a target for immunomodulatory treatment in NVAMD.
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Affiliation(s)
- Yue Zou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China
- The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, 200032, China
- Department of Ophthalmology, Yunnan Eye Institute & Key Laboratory of Yunnan Province, Yunnan Eye Disease Clinical Medical Center, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, 650021, China
| | - Junliang Jiang
- Department of Orthopedics & Traumatology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, 650021, China
| | - Yunqin Li
- Department of Ophthalmology, Yunnan Eye Institute & Key Laboratory of Yunnan Province, Yunnan Eye Disease Clinical Medical Center, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, 650021, China
| | - Xinyi Ding
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China
| | - Qiuping Tong
- The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Ying Shi
- The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Lei Xiao
- The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Ling Chen
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China
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11
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He L, He J, Jiang T, Gong R, Wan X, Duan M, Chen Z, Cheng Y. Inhibition of UCH-L1 enhances immunotherapy efficacy in triple-negative breast cancer by stabilizing PD-L1. Eur J Pharmacol 2025; 1000:177743. [PMID: 40389130 DOI: 10.1016/j.ejphar.2025.177743] [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: 01/28/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
Recent research indicates that programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors show promise in treating triple-negative breast cancer (TNBC), but their efficacy is lower than anticipated, especially when used alone. Therefore, enhancing the anti-tumor immune response strategy for TNBC is crucial. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), involved in tumor cell regulation and a potential therapeutic target, has an undefined role in TNBC immunotherapy. In this study, we explored the inverse correlation between UCH-L1 and PD-L1 in TNBC patient tissues. Through in vitro experiments, we found that UCH-L1 negatively regulates PD-L1 by stabilizing the E3 ubiquitin ligase ariadne-1 homolog (ARIH1), which promotes PD-L1 ubiquitination and degradation. Further analysis in Balb/c mice xenograft tumors showed that UCH-L1 correlates with GZMB+/CD8+ T cell infiltration in TNBC, suggesting potential synergistic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. Overall, in TNBC, UCH-L1 stabilizes ARIH1, leading to low PD-L1 expression, which may explain the limited effectiveness of immunotherapy in TNBC patients. Our mouse experiments showed improved therapeutic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. These findings offer a new avenue for immunotherapy in TNBC patients.
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Affiliation(s)
- Linhao He
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Jiaying He
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ting Jiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Rong Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Xiaoya Wan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Mingwu Duan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Zonglin Chen
- Clinical Research Center for Breast Disease in Hunan Province, Changsha, 410011, China
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China; Clinical Research Center for Breast Disease in Hunan Province, Changsha, 410011, China; NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, China; Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, 410011, China.
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12
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Gholamin S, Natri HM, Zhao Y, Xu S, Aftabizadeh M, Comin-Anduix B, Saravanakumar S, Masia C, Wong RA, Peter L, Chung MI, Mee ED, Aguilar B, Starr R, Torrejon DY, Alizadeh D, Wu X, Kalbasi A, Ribas A, Forman S, Badie B, Banovich N, Brown C. Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.01.646202. [PMID: 40236117 PMCID: PMC11996542 DOI: 10.1101/2025.04.01.646202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Chimeric antigen receptor CAR T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment TME, characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood. Here, we conducted single-cell RNA sequencing scRNA seq on tumors from 41 glioma patients undergoing IL13Ra2-targeted CAR T cell therapy, identifying elevated suppressive SPP1 signatures predominantly in macrophages from patients who were resistant to treatment. Further integrative scRNA seq analysis of high-grade gliomas as well as an interferon-signaling deficient syngeneic mouse model both resistant to CAR T therapy demonstrated the role of congruent suppressive pathways in mediating resistance to CAR T cells and a dominant role for SPP1+ macrophages. SPP1 blockade with an anti-SPP1 antibody abrogates the suppressive TME effects and substantially prolongs survival in IFN signaling-deficient and glioma syngeneic mouse models resistant to CAR T cell therapy. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Targeting SPP1 may serve as a universal strategy to reprogram immune dynamics in solid tumors mitigating resistance to CAR T therapies.
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13
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Sun F, Gao X, Wang W, Zhao X, Zhang J, Zhu Y. Predictive biomarkers in the era of immunotherapy for gastric cancer: current achievements and future perspectives. Front Immunol 2025; 16:1599908. [PMID: 40438098 PMCID: PMC12116377 DOI: 10.3389/fimmu.2025.1599908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 04/24/2025] [Indexed: 06/01/2025] Open
Abstract
Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.
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Affiliation(s)
- Fujing Sun
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaozhuo Gao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Wentao Wang
- Department of Gastric Surgery, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaoyan Zhao
- Department of Gynecology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
- Graduate School, Dalian Medical University, Dalian, China
| | - Jingdong Zhang
- Department of Gastroenterology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
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14
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Huang X, Qu F, Ma Y, Lin H. Homologous Boron Nitride Heterostructure: Piezoelectricity, Catalysis, and Nitric Oxide Release to Reprogram the Tumor Microenvironment for Anticancer. ACS APPLIED MATERIALS & INTERFACES 2025. [PMID: 40367364 DOI: 10.1021/acsami.5c04807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
The tumor microenvironment (TME) inherently exhibits treatment resistance, which restrains the therapeutic effect. Here, intracellular piezoelectric catalysis and stepwise nitric oxide (NO) release were integrated to modulate the TME for anticancer therapy. A piezoelectric homologous boron nitride (BN) heterostructure (BN3:1) was prepared, which promotes the piezoelectric character and facilitates the spatial separation of ultrasound (US)-generated charges. The electrons dominate reactive oxygen species (ROS) generation, and the holes also consume endogenous glucose and nicotinamide adenine dinucleotide phosphate (NADPH). The simultaneous reactions of electrons and holes not only facilitate charge separation but also disrupt TME metabolism. In addition, BN3:1 releases NO in response to TME-specific H+/H2O2. Under US irradiation, increased ROS generation boosts NO release to damage DNA/mitochondria and decompose the extracellular matrix (ECM). Without US, moderate NO release is conducive to vascular normalization, hypoxia relief, and PD-L1 downregulation. Furthermore, intracellular NO microbubbles amplify US imaging contrast, endowing efficient monitoring of NO release in vitro and in vivo. It is the first time employing BN nanosheets as sonosensitizers and NO donors. The synergistic effect grants great anticancer efficiency, which can also arouse an anticancer immune response to further fight against metastasis and recurrence.
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Affiliation(s)
- Xinyan Huang
- Key Laboratory of Photochemical Biomaterials and Energy Storage Materials, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Fengyu Qu
- Key Laboratory of Photochemical Biomaterials and Energy Storage Materials, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Yajie Ma
- Key Laboratory of Photochemical Biomaterials and Energy Storage Materials, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Huiming Lin
- Key Laboratory of Photochemical Biomaterials and Energy Storage Materials, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
- Laboratory for Photon and Electronic Bandgap Materials, Ministry of Education, Harbin Normal University, Harbin 150025, China
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15
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Li Q, Liu C, Fan Z, Zhang H, Kai Z. Computed tomography-based conventional imaging features and texture analysis characteristics of chemotherapy drug-related acute pancreatitis. Front Med (Lausanne) 2025; 12:1497944. [PMID: 40421297 PMCID: PMC12104288 DOI: 10.3389/fmed.2025.1497944] [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: 11/18/2024] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Purpose Chemotherapy drug-related acute pancreatitis (CDRAP) is a rare adverse event that poses significant challenges to clinicians. This study aimed to describe plain computed tomography (CT)- and contrast-enhanced computed tomography (CECT)-based conventional imaging features and texture analysis characteristics of CDRAP. Methods A total of 62 patients with initial clinical and/or biochemical evidence of pancreatitis and 34 patients with normal pancreatic manifestations who underwent CT during chemotherapy were retrospectively included. The diagnosis of CDRAP was established based on clinical, imaging, and biochemical findings. Conventional imaging features, texture analysis characteristics, clinical and biochemical parameters, other complications, chemotherapy drugs, and patient outcomes related to CDRAP were recorded. Results A total of 20 (32.26%) patients who were clinically diagnosed with CDRAP had normal pancreatic morphology on CT, while 42 (67.74%) patients presented with changes indicative of acute pancreatitis. The CT findings of 62 CDRAP cases were as follows: diffuse (n = 19) or focal (n = 21) pancreatic enlargement, diffuse (n = 12) or focal (n = 4) heterogeneous enhancement, peripancreatic stranding (n = 20), acute peripancreatic fluid collection (n = 10), and pseudocyst (n = 2). A total of 17 texture features were identified to differentiate CDRAP from normal pancreatic manifestations. Conclusion CDRAP mainly manifested as interstitial edematous pancreatitis with/without normal pancreatic morphology on CT. Imaging texture analysis may serve as a potential biomarker for its detection. By combining conventional imaging features with texture analysis characteristics, there is potential to assist radiologists and clinicians in the identification of CDRAP, thereby improving the quality of life for cancer patients.
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Affiliation(s)
- Quanlin Li
- Department of Radiology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China
| | - Chuanmei Liu
- Department of Radiology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China
| | - Zijian Fan
- Department of Radiology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China
| | - Hong Zhang
- Department of Radiology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China
| | - Zhiguo Kai
- Department of Radiology, The 4th People’s Hospital of Jinan, Jinan, China
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16
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Guo Z, Chen D, Yao L, Sun Y, Li D, Le J, Dian Y, Zeng F, Chen X, Deng G. The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer. Signal Transduct Target Ther 2025; 10:149. [PMID: 40341098 PMCID: PMC12062509 DOI: 10.1038/s41392-025-02192-0] [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: 09/06/2024] [Revised: 12/13/2024] [Accepted: 02/17/2025] [Indexed: 05/10/2025] Open
Abstract
Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.
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Affiliation(s)
- Ziyu Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Danyao Chen
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Yao
- Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daishi Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Jiayuan Le
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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17
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Li A, Luo M, Liu X, Wu H, Liu X, Zhang Z, Zhang X. Toll-like receptor 3 activation enhances antitumor immune response in lung adenocarcinoma through NF-κB signaling pathway. Front Immunol 2025; 16:1585747. [PMID: 40406122 PMCID: PMC12095255 DOI: 10.3389/fimmu.2025.1585747] [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: 03/01/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
Background Toll-like receptor 3 (TLR3) is a pattern recognition receptor known to play a crucial role in the immune response to cancer. However, its effect on the efficacy of immunotherapy in lung adenocarcinoma (LUAD) remains unclear. This study aims to investigate the role of TLR3 in LUAD by examining its expression levels, prognostic significance, and impact on immune signaling pathways. Methods We analyzed the impact of TLR3 expression on the prognosis of lung adenocarcinoma patients using data from the Cancer Genome Atlas (TCGA) database and four additional cohorts (GSE72094, GSE30219, GSE50081 and GSE31210). Functional enrichment analyses were performed to compare molecular features between low and high TLR3 expression groups using gene set variation analysis (GSVA). We also examined the correlation between TLR3 and tumor mutation burden (TMB), immune infiltration, and PD-L1 expression. Further experimental validation was conducted using co-culture systems of LUAD cells and peripheral blood mononuclear cells (PBMCs) with PD1 inhibitors, and Western blot analysis to investigate the involvement of NF-κB signaling. Results TLR3 expression was significantly lower in LUAD tissues compared to normal tissues, with high TLR3 expression correlating with better survival outcomes across multiple cohorts. High TLR3 expression was associated with increased TMB and enhanced immune activation. Patients with high TLR3 expression exhibited higher immune checkpoint expression and immune cell infiltration. Experimental results showed that TLR3 agonists increased the susceptibility of LUAD cells to activated PBMCs under PD1 inhibitor therapy, inhibiting cell proliferation, migration, and invasion. Additionally, TLR3 has a strong positive correlation with MHC molecules and upregulated PD-L1 expression. NF-κB was identified as a key regulator of PD-L1 expression, with TLR3 agonists enhancing NF-κB and PD-L1 activity. Conclusion TLR3 enhances the anti-tumor immune response in LUAD by modulating NF-κB signaling and PD-L1 expression, making it a promising prognostic biomarker and therapeutic target. This study highlights the potential of TLR3 to improve immunotherapy outcomes, providing a comprehensive analysis of its role in LUAD and paving the way for novel therapeutic strategies targeting TLR3-mediated pathways.
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Affiliation(s)
- Ang Li
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
| | - Man Luo
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Xiyao Liu
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Hongjiao Wu
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
| | - Xiaoguang Liu
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Zhi Zhang
- Affliated Tangshan Gongren Hospital, North China University of Science and Technology, Tangshan, China
| | - Xuemei Zhang
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
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18
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Zhang Q, Zhang Y, Sun Z, Wang H, Dai G, Meng Y, Shi S, Ren S. Integrated analysis identifies P4HA2 as a key regulator of STAT1-mediated colorectal cancer progression and a potential biomarker for precision therapy. Front Oncol 2025; 15:1581860. [PMID: 40406250 PMCID: PMC12094996 DOI: 10.3389/fonc.2025.1581860] [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: 02/23/2025] [Accepted: 04/15/2025] [Indexed: 05/26/2025] Open
Abstract
Introduction P4HA2 is implicated in regulating tumor microenvironment formation and may play roles in inflammation and tumor immunity. However, its mechanistic involvement in colorectal cancer (CRC) remains largely unexplored. Methods We analyzed P4HA2 expression in CRC tissues and correlated it with clinicopathological features. Functional assays (CCK8, wound healing, Transwell) were performed to assess proliferation and migration. Proteomic analysis identified downstream targets, with STAT1/PD-L1 pathway validation. Results High P4HA2 expression correlated with advanced T/M stages and served as an independent poor prognostic factor. Functional experiments confirmed P4HA2's role in promoting CRC proliferation and migration. Mechanistically, P4HA2 bound to and downregulated STAT1, subsequently modulating the STAT1/PD-L1 pathway. Discussion Our findings reveal P4HA2 promotes CRC progression and suppresses anti-tumor immunity via STAT1/PD-L1 axis regulation. This study uncovers a novel pathogenic mechanism, positioning P4HA2 as a potential therapeutic target in CRC.
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Affiliation(s)
- Qianshi Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yinan Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhiwei Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huanle Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guohang Dai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yue Meng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shasha Shi
- Department of Ultrasound, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shuangyi Ren
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Yan Z, Wang C, Wu J, Wang J, Ma T. TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives. MOLECULAR BIOMEDICINE 2025; 6:27. [PMID: 40332725 PMCID: PMC12058639 DOI: 10.1186/s43556-025-00267-6] [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: 08/02/2024] [Revised: 04/13/2025] [Accepted: 04/18/2025] [Indexed: 05/08/2025] Open
Abstract
Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, the efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several immune checkpoint proteins are presently being thoroughly screened and assessed in both preclinical and clinical studies. Among these candidates, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is considered a promising target. TIM-3 exhibits multiple immunosuppressive effects on various types of immune cells. Given its differential expression levels at distinct stages of T cell dysfunction in the tumor microenvironment (TME), TIM-3, along with programmed cell death protein 1 (PD-1), serves as indicators of T cell exhaustion. Moreover, it is crucial to carefully evaluate the impact of TIM-3 and PD-1 expression in cancer cells on the efficacy of immunotherapy. To increase the effectiveness of anti-TIM-3 and anti-PD-1 therapies, it is proposed to combine the inhibition of TIM-3, PD-1, and programmed death-ligand 1 (PD-L1). The efficacy of TIM-3 inhibition in conjunction with PD-1/PD-L1 inhibitors is being evaluated in a number of ongoing clinical trials for patients with various cancers. This study systematically investigates the fundamental biology of TIM-3 and PD-1, as well as the detailed mechanisms through which TIM-3 and PD-1/PD-L1 axis contribute to cancer immune evasion. Additionally, this article provides a thorough analysis of ongoing clinical trials evaluating the synergistic effects of combining PD-1/PD-L1 and TIM-3 inhibitors in anti-cancer treatment, along with an overview of the current status of TIM-3 and PD-1 antibodies.
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Affiliation(s)
- Zhuohong Yan
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Chunmao Wang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Jinghong Wu
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Jinghui Wang
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Teng Ma
- Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
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20
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Ren Q, Wang F, Du F, He C, Wang X, Wang J, Zhang Z, Sun Y. Asiaticoside enhances the anti-tumor effect of anti-PDL1 by regulating T cell activity through increasing LCK activity. Pathol Res Pract 2025; 271:155995. [PMID: 40373489 DOI: 10.1016/j.prp.2025.155995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 03/12/2025] [Accepted: 05/05/2025] [Indexed: 05/17/2025]
Abstract
Anti-PD-L1 antibody confers anti-tumor effects, but its long-term use can provoke resistance and adverse effects. Asiaticoside, a bioactive triterpene glycoside from Centella asiatica L., regulates immune function and induces apoptosis of hepatocellular carcinoma (HCC) cells. T cells play a vital role in killing tumor cells and require lymphocyte-specific protein tyrosine kinase (LCK) for activation. Here, we examined whether a combined asiaticoside and anti-PD-L1 treatment regulates T cells via LCK activation to enhance the anti-tumor effect in vivo. We established a subcutaneous mouse HCC model using Hepa1-6 cells and measured spleen and tumor weight. Morphological changes of tumor tissues were assessed by hematoxylin-eosin staining. Tumor cell apoptosis and proliferation were determined by TUNEL staining and KI67 immunohistochemistry. The proportion of activated T cells in the spleen was detected by flow cytometry, and the levels of phosphorylated p-LCK and p-AKT in the spleen were determined by Western blotting. Changes in the levels of serum inflammatory factors were detected with ELISA. Our results revealed that the combined asiaticoside and anti-PD-L1 treatment inhibited tumor growth by enhancing apoptosis and reducing tumor cell proliferation. The treatment activated T cells to increase the proportion of effector T cells in the spleen, evidenced by upregulated p-LCK and p-AKT levels. It also increased the level of TNF-α in the serum and decreased IL-6, implying an enhanced immune response. In conclusion, the combined asiaticoside and anti-PD-L1 treatment enhances the anti-HCC effect in vivo by promoting LCK activation to regulate T cells.
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Affiliation(s)
- Qingyi Ren
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Fang Wang
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, China; Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China; Central Nervous System Drug Key Laboratory of Sichuan Province
| | - Fei Du
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Chenxi He
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiaodong Wang
- Department of Hepatobiliary Disease, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Jun Wang
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, China; Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhuo Zhang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Yuhong Sun
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
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21
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Chen D, Zhao Z, Hong R, Yang D, Gong Y, Wu Q, Wang Y, Cao Y, Chen J, Tai Y, Liu H, Li J, Fan J, Zhang W, Song Y, Zhan Q. Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy. Nat Commun 2025; 16:4128. [PMID: 40319089 PMCID: PMC12049493 DOI: 10.1038/s41467-025-59318-9] [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: 08/15/2024] [Accepted: 04/17/2025] [Indexed: 05/07/2025] Open
Abstract
The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.
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Affiliation(s)
- Dongshao Chen
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Zitong Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoxi Hong
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Di Yang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Gong
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Qingnan Wu
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Wang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yiren Cao
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Chen
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yidi Tai
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Haoyu Liu
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jinting Li
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiawen Fan
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Weimin Zhang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.
| | - Yongmei Song
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Qimin Zhan
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.
- International Cancer Institute, Peking University Health Science Center, Beijing, China.
- Soochow University Cancer institute, Suzhou, Jiangsu, China.
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22
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Zhang R, Zhang X, Lau HCH, Yu J. Gut microbiota in cancer initiation, development and therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1283-1308. [PMID: 39821827 DOI: 10.1007/s11427-024-2831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.
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Affiliation(s)
- Ruyi Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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23
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Chan SWS, Pond GR, Goffin JR. The Impact of Chronic Obstructive Pulmonary Disease on Immune Checkpoint Inhibitor Effectiveness in Non-small Cell Lung Cancer: A Population Health Study. J Immunother 2025; 48:138-146. [PMID: 39976181 DOI: 10.1097/cji.0000000000000551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 02/05/2025] [Indexed: 02/21/2025]
Abstract
SUMMARY Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD confers a negative prognosis in NSCLC, but the clinical benefit of immune checkpoint inhibitors (ICI) in this population is unclear. A population-level analysis of patients in Ontario, Canada was performed through the ICES (formerly known as the Institute for Clinical Evaluative Sciences) administrative database. Patients with NSCLC and treated with PD-1/PD-L1 immune checkpoint inhibitors between Jan 2010 and Dec 2020 were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using Cox proportional hazards regression. Hospitalizations and duration of treatment were compared secondarily using logistic and linear regression. A total of 4306 patients received ICI and 54% of patients had a diagnosis of COPD. Median (95% CI) OS was 9.2 (8.5-9.9) months for patients with COPD and 8.2 (7.3-8.8) for patients without COPD, which was not significantly different (adjusted hazard ratio (aHR) = 0.94, 95% CI, 0.87-1.01, P = 0.092). Similarly, the median time on treatment was not different (85 vs. 99 days, multivariable P = 0.10). However, the 90-day hospitalization rate was decreased in the COPD population (multivariable odds ratio 0.76, 95% CI 0.62-0.94, P = 0.011). Among patients with NSCLC receiving ICI, our data suggest that a diagnosis of COPD does not result in shortened treatment, poorer survival, or higher rates of hospitalization. COPD itself should not be considered a contraindication to ICI.
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24
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Wu M, Liu J, Liu L, Yang Y, Liu H, Yu L, Zeng H, Yuan S, Xu R, Liu H, Jiang H, Qu S, Wang L, Chen Y, Wang J, Zhang Y, He S, Feng L, Han J, Zeng W, Wang H, Huang Y. Autologous Peripheral Vγ9Vδ2 T Cell Synergizes with αβ T Cell Through Antigen Presentation and BTN3A1 Blockade in Immunotherapy of Cervical Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2401230. [PMID: 40091603 PMCID: PMC12079532 DOI: 10.1002/advs.202401230] [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] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/07/2025] [Indexed: 03/19/2025]
Abstract
New treatment strategies are urgently needed for patients with advanced cervical cancer (CC). Here, a synergistic anti-CC effect of a novel combinatorial immunotherapy with adoptively transferred autologous Vγ9Vδ2 T cells and αβ T cells is shown. The pivotal role of both circulating and tumor-infiltrating Vγ9Vδ2 T cells in anti-CC immunity is uncovered. Importantly, autologous Vγ9Vδ2 T cells show a synergistic anti-CC effect with αβ T cells not only through killing tumor directly, but also by promoting the activation and tumoricidal activity of syngeneic αβ T cells through antigen presentation, which can be further boosted by conventional chemotherapy. Moreover, Vγ9Vδ2 T cells can restore the tumoricidal function of αβ T cell through competitively binding to BTN3A1, a TCR-Vγ9Vδ2 ligand on CC cells upregulated by IFN-γ derived from activated αβ T cell. These findings uncover a critical synergistic effect of autologous Vγ9Vδ2 T cells and αβ T cells in immunotherapy of CC and reveal the underlying mechanisms.
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Affiliation(s)
- Min Wu
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Jian Liu
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Liting Liu
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Yifan Yang
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Hong Liu
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Long Yu
- Beckman Coulter Commercial Enterprise (China) Co., LtdShanghai200122China
| | - Haihong Zeng
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Shuo Yuan
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Ruiyi Xu
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Hangyu Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Han Jiang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Shen Qu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Liming Wang
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Ying Chen
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Jingyu Wang
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yuwei Zhang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Shan He
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Ling Feng
- Department of Obstetrics and Gynecology, Tongji Hospital and School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Junyan Han
- Department of Immunology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Wanjiang Zeng
- Department of Obstetrics and Gynecology, Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Hui Wang
- Department of Obstetrics and GynecologyTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyCancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Department of Gynecologic Oncology, Women's HospitalZhejiang University School of MedicineZhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Yafei Huang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science and TechnologyWuhan430030China
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25
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Lian C, Liu Y, Lei P. miR-186-5p Down-Regulates PD-L1 Level in Acute Myeloid Leukemia Cells and Inhibits Tumorigenesis and Immune Escape. J Biochem Mol Toxicol 2025; 39:e70278. [PMID: 40285500 DOI: 10.1002/jbt.70278] [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: 10/30/2024] [Revised: 03/07/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
Acute myeloid leukemia (AML) is a malignant tumor of blood cells, which seriously interferes with the generation of normal cells. Although miR-186-5p is diminished in AML, its exact mechanism is not well understood. miR-186-5p and PD-L1 levels in AML cells (HL-60, KG-1, TF-1a, MOLT-3) and subcutaneous tumor tissue were discovered through qRT-PCR and Western blot. miR-186-5 p and PD-L1 combining sites were foreseen by the database and verified by dual luciferase and immunoprecipitation experiments. AML cells with miR-186-5p overexpression or knockdown and PD-L1 overexpression were cocultured with CD4+ and CD8+ T cells. The proliferation, migration, invasion and apoptosis of AML cells, CD8+ and CD4+ T cell growth and apoptosis, and activated markers (Perforin and Granzyme B) and secreted cytokines (IFN-γ, IL-4 and TNF-α) levels were detected by CCK8, Transwell, flow cytometry, CFSE, Western blot and ELISA, respectively. Subcutaneous xenograft magnitude and mass in nude mice were measured. Ki67 level was identified through immunohistochemistry. CD4+ and CD8+ T cell level and infiltration were detected by immunofluorescence and flow cytometry. miR-186-5p was downregulated, and PD-L1 was boosted in AML cells and subcutaneous tumor tissues (p < 0.05), while miR-186-5p targeted down-regulate PD-L1. miR-186-5p upregulation hindered AML cell multiplication, migration, invasion and facilitate cell death, and enhanced the proliferation activity, activation markers (Perforin and Granzyme B) and secreted cytokines (IFN-γ, IL-4, TNF-α) of CD8+ and CD4+ T cells, inhibited apoptosis, and inhibited immune escape (p < 0.05). Knockdown of miR-186-5p can promote AML progression, but PD-L1 upregulation weakens the antitumor impact of miR-186-5p overexpression (p < 0.05). Transplanted tumor mice experiments also found that miR-186-5p hindered PD-L1 and tumor growth (p < 0.05). In conclusion, miR-186-5p can target inhibit PD-L1, suppress AML cells multiplication, movement, invasion and immune escape, and then reduce AML, aiming to provide support and basis for the pathological mechanism and prevention and treatment strategy of AML.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/immunology
- MicroRNAs/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/genetics
- Humans
- Animals
- B7-H1 Antigen/genetics
- B7-H1 Antigen/metabolism
- B7-H1 Antigen/immunology
- Down-Regulation
- Mice
- Mice, Nude
- Carcinogenesis/genetics
- Carcinogenesis/immunology
- Carcinogenesis/pathology
- HL-60 Cells
- Cell Proliferation
- Tumor Escape
- Apoptosis
- Cell Line, Tumor
- RNA, Neoplasm/genetics
- RNA, Neoplasm/immunology
- RNA, Neoplasm/metabolism
- Female
- Male
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Proteins/metabolism
- CD8-Positive T-Lymphocytes/immunology
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Affiliation(s)
- Cheng Lian
- Department of Hematology, Henan provincial People's Hospital, Zhengzhou, Henan, China
| | - Yanhui Liu
- Department of Hematology, Henan provincial People's Hospital, Zhengzhou, Henan, China
| | - Pingchong Lei
- Department of Hematology, Henan provincial People's Hospital, Zhengzhou, Henan, China
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26
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Wang Y, Guo T, Xing X, Liu X, Gan X, Li Y, Liu Y, Shan F, Wu Z, Ji J, Li Z. The accumulation of myeloid-derived suppressor cells participates in abdominal infection-induced tumor progression through the PD-L1/PD-1 axis. Mol Oncol 2025; 19:1532-1545. [PMID: 39835710 PMCID: PMC12077272 DOI: 10.1002/1878-0261.13767] [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: 05/07/2024] [Revised: 09/20/2024] [Accepted: 11/07/2024] [Indexed: 01/22/2025] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with gastrectomy being the primary treatment option. Sepsis, a systemic inflammatory response to infection, may influence tumor growth by creating an immunosuppressive environment conducive to cancer cell proliferation and metastasis. Here, the effect of abdominal infection on tumor growth and metastasis was investigated through the implementation of a peritoneal metastasis model and a subcutaneous tumor model. In a murine model induced by cecal ligation and puncture (CLP) to simulate the effects of sepsis, we observed significant immune dysregulation, including T-cell exhaustion and the release of myeloid-derived suppressor cells (MDSCs). This immune alteration was associated with increased programmed cell death protein 1 (PD-1) expression on T cells and programmed cell death 1 ligand 1 (PD-L1) expression on MDSCs within the tumor microenvironment, fostering an immune-suppressive environment. Polymorphonuclear MDSCs (PMN-MDSCs) expressing elevated PD-L1 after sepsis demonstrated more substantial suppressive effects on T-cell proliferation than controls. Treatment with anti-PD-1 monoclonal antibodies successfully restored T-cell function, reduced mortality, and decreased metastasis in CLP mice. These findings emphasize the impact of sepsis on tumor progression and suggest targeting the PD-1/PD-L1 axis as a potential therapeutic strategy for managing immune dysfunction in patients with cancer.
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Affiliation(s)
- Yiding Wang
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Ting Guo
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
| | - Xiaofang Xing
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
| | - Xijuan Liu
- Department of Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Xuejun Gan
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Yingai Li
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Yan Liu
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Fei Shan
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Zhouqiao Wu
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Jiafu Ji
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Ziyu Li
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingChina
- Department of Gastrointestinal Cancer CenterPeking University Cancer Hospital & InstituteBeijingChina
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Chen R, Li Z, Fang Z, Li Z, Yang D, Li Y, Liu S, Liu Z, Liu R, Liu H. Chemotherapy-Mediated Induction of PD-L1 via SEI1 Facilitates Myeloma Immune Evasion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411082. [PMID: 40135791 PMCID: PMC12097018 DOI: 10.1002/advs.202411082] [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] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/19/2025] [Indexed: 03/27/2025]
Abstract
Multiple myeloma (MM) is a plasma cell-derived malignancy. While immune checkpoint blockade immunotherapy has advanced myeloma treatment, chemotherapy remains the primary therapy. How chemotherapy interacts with immune checkpoint expression and impacts immunotherapy efficacy remains unclear. Here it is discovered that chemotherapeutic drugs induce DNA damage and activate the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. This activation promotes phosphorylation of the interferon regulatory factor 7 (IRF7), which binds to the promoter region of SERTA-containing domain 1 (SERTAD1, also called SEI1) gene to enhance its transcription. The SEI1 directly interacts with the enhancer factors CREB-binding protein (CBP)/p300 and RNA polymerase II (pol II)-associated factor 1 (PAF1) complex, promoting transcriptional activity and leading to upregulation of programmed death ligand-1 (PD-L1) and immune escape in myeloma. Both in vitro and in vivo experiments demonstrate that treating myeloma cells with PD-L1 antibodies post-chemotherapy significantly enhances the killing efficiency of activated T cells, compared to sequential treatment with chemotherapy and PD-L1 antibodies. This research not only uncovers a pivotal regulatory mechanism of PD-L1 upregulation but also provides a compelling rationale for the integration of chemotherapy and immunotherapy in myeloma treatment.
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Affiliation(s)
- Rui Chen
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Zongwei Li
- School of Life SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Zhihong Fang
- Department of HematologyThe First Affiliated Hospital of Xiamen University and Institute of HematologySchool of MedicineXiamen UniversityXiamen361102China
- Department of HematologyKey Laboratory of Xiamen for Diagnosis and Treatment of Hematological MalignancyXiamen361102China
| | - Zou Li
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Daoyan Yang
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Yuan Li
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Shurong Liu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Zhiqiang Liu
- Shandong Provincial Key Laboratory of Radiation OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinan250117China
| | - Rui Liu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
| | - Huan Liu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361102China
- Department of HematologyThe First Affiliated Hospital of Xiamen University and Institute of HematologySchool of MedicineXiamen UniversityXiamen361102China
- Shenzhen Research Institute of Xiamen UniversityShenzhenGuangdong518057China
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Yang QC, Wang YY, Wang S, Song A, Wang WD, Zhang L, Sun ZJ. Engineered bacterial membrane biomimetic covalent organic framework as nano-immunopotentiator for cancer immunotherapy. Bioact Mater 2025; 47:283-294. [PMID: 39925708 PMCID: PMC11803166 DOI: 10.1016/j.bioactmat.2025.01.018] [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: 09/23/2024] [Revised: 12/27/2024] [Accepted: 01/15/2025] [Indexed: 02/11/2025] Open
Abstract
The cellular uptake and tissue dispersion efficiency of nanomedicines are crucial for realizing their biological functionality. As a cutting-edge category of nanomedicine, covalent organic frameworks (COFs)-based photosensitizers, have been extensively employed in cancer phototherapy in recent years. However, the inherent aggregation tendency of COFs hinders their uptake by tumor cells and dispersion within tumor tissues, thereby limiting their therapeutic efficacy. In this study, we employed Fusobacterium nucleatum (F.n.), a prevalent intratumoral bacterium, to construct a bacterium membrane-wrapped COF, COF-306@FM, which is readily taken up by cancer cells and uniformly dispersed within tumor tissues. Meanwhile, the F.n. membrane can also serve as an immune adjuvant to warm up the "cold" tumor immune microenvironment by enhancing the CD8+ T and B cells infiltration, and inducing the formation of tumor-located tertiary lymphoid structures. Consequently, the response rate of αPD-L1 immunotherapy was drastically promoted to efficiently prevent tumor metastasis and recurrence, causing 84.6 % distant tumor inhibition and complete suppression of tumor metastasis. In summary, this innovative approach not only enhances the therapeutic potential of COFs but also opens up new avenues for integrating microbial and nanotechnological strategies in cancer treatment.
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Affiliation(s)
- Qi-Chao Yang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - Yuan-Yuan Wang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - Shuo Wang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - An Song
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - Wen-Da Wang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - Liang Zhang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
| | - Zhi-Jun Sun
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China
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29
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Bai L, Liu X, Yuan Z, Xu G, Li X, Wan Z, Zhu M, Liang X, Li P, Lan Q, Yu H, Tang G, Huang M, Peng S, Lin J, Wang X, Luo Y, Wei G. Activation of IL-2/IL-2R pathway by Hedyotis diffusa polysaccharide improves immunotherapy in colorectal cancer. Int J Biol Macromol 2025; 306:141013. [PMID: 39954887 DOI: 10.1016/j.ijbiomac.2025.141013] [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: 09/02/2024] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/17/2025]
Abstract
Colorectal cancer (CRC) is a prevalent and highly malignant tumor with a limited response to immune checkpoint inhibitor-based immunotherapy. There is an urgent need for novel immunomodulatory agents to enhance the immunotherapeutic response in CRC. Hedyotis diffusa, known for its immunomodulatory properties, has long been utilized as an adjunct in cancer treatment, positioning it as a potential source for discovering new tumor immunomodulators. In this study, we identified a polysaccharide derived from Hedyotis diffusa (HDP), comprising six monosaccharides: rhamnose, arabinose, galactose, glucose, xylose, and mannose. When combined with PD-1 and CTLA-4 inhibitors, HDP can boost systemic immunity in mice to enhance the effectiveness of immune checkpoint inhibitors in CRC therapy. HDP significantly increases the infiltration of CD4+ and CD8+ T cells into tumor microenvironment and upregulates the expression of key effector molecules derived from cytotoxic T cells. Mechanistic studies reveal that HDP activates the IL-2/IL-2R axis by upregulating IL-2 production and the expression of IL-2 receptor subunits, thereby promoting T cell proliferation. Collectively, this research introduces an innovative strategy to improve the efficacy of tumor immunotherapy by harnessing the immunomodulatory potential of polysaccharides. It also directs a roadmap for developing HDP as a promising immunomodulator for CRC treatment.
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Affiliation(s)
- Liangliang Bai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Xiaoxia Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Ze Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Gaopo Xu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xuan Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Zhongxian Wan
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei 445000, China
| | - Mingxuan Zhu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiaoxia Liang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Peisi Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Qiqian Lan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Huichuan Yu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Guannan Tang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Mingzhe Huang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Shaoyong Peng
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jinxing Lin
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiaolin Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Yanxin Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Gang Wei
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
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30
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Barba A, López-Vilaró L, Ferre M, Martinez-Recio S, Majem M, Sullivan I, Salazar J. CD274 ( PD-L1) Polymorphisms as Predictors of Efficacy in First-Line Platinum-Based Chemotherapy for Extensive-Stage Small Cell Lung Cancer. Int J Mol Sci 2025; 26:4245. [PMID: 40362483 PMCID: PMC12072405 DOI: 10.3390/ijms26094245] [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: 03/19/2025] [Revised: 04/22/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29-0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09-0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23-0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14-0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02-0.70; p = 0.02, and OR 0.08, 95% CI 0.01-0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC.
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Affiliation(s)
- Andrés Barba
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (A.B.); (S.M.-R.); (M.M.); (I.S.)
- Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain
| | - Laura López-Vilaró
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (L.L.-V.); (M.F.)
| | - Malena Ferre
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (L.L.-V.); (M.F.)
| | - Sergio Martinez-Recio
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (A.B.); (S.M.-R.); (M.M.); (I.S.)
- Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain
| | - Margarita Majem
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (A.B.); (S.M.-R.); (M.M.); (I.S.)
- Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain
| | - Ivana Sullivan
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (A.B.); (S.M.-R.); (M.M.); (I.S.)
- Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain
| | - Juliana Salazar
- Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain
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Guo X, Zhang Y, Liu Q, Xu M, Pang J, Yang B, Rong S, Yang X. Progress on liposome delivery systems in the treatment of bladder cancer. RSC Adv 2025; 15:14315-14336. [PMID: 40330044 PMCID: PMC12053965 DOI: 10.1039/d5ra00746a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Bladder cancer (BC) in the urinary system remains one of the most prevalent malignancies with high recurrence rate globally. Current treatment schemes against BC such as surgery, chemotherapy, and radiotherapy have substantial limitations including side effects, drug resistance, and poor tumor targeting. Considering the above-mentioned challenges, nanotechnology has become a current research hotspot, particularly liposome-based drug delivery systems, which offer promising novel therapeutic strategies aimed at reducing systemic toxicity, overcoming drug resistance, and enhancing drug targeting. This review systematically elaborates the current research progress on liposomal drug delivery systems in BC treatment, focusing on their application in chemotherapy, immunotherapy, and gene therapy. Additionally, we provide a comprehensive assessment of the benefits and limitations of liposome nanocarriers used in BC treatment. The advanced targeting strategies and combination treatments via liposomal therapies are also discussed, demonstrating that liposomal formulations have great potential application value in the treatment of BC owing to their superior bioavailability, stability, and targeting and minimal adverse effects.
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Affiliation(s)
- Xinyu Guo
- Department of Urology Surgery, First Hospital of Shanxi Medical University Taiyuan Shanxi 030001 China
- The First Clinical Medical College of Shanxi Medical University Taiyuan Shanxi 030001 China
| | - Yan Zhang
- School of Optoelectronic Engineering, Xi'an Technological University Xi'an 710021 China
| | - Quanyong Liu
- Department of Urology Surgery, First Hospital of Shanxi Medical University Taiyuan Shanxi 030001 China
- The First Clinical Medical College of Shanxi Medical University Taiyuan Shanxi 030001 China
| | - Mingquan Xu
- Department of Urology Surgery, First Hospital of Shanxi Medical University Taiyuan Shanxi 030001 China
- The First Clinical Medical College of Shanxi Medical University Taiyuan Shanxi 030001 China
| | - Jianzhi Pang
- The First Clinical Medical College of Shanxi Medical University Taiyuan Shanxi 030001 China
| | - Bin Yang
- Department of Urology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital Taiyuan 030032 China
| | - Shuo Rong
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital Taiyuan 030032 China
| | - Xiaofeng Yang
- Department of Urology Surgery, First Hospital of Shanxi Medical University Taiyuan Shanxi 030001 China
- The First Clinical Medical College of Shanxi Medical University Taiyuan Shanxi 030001 China
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32
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Li L, Zeng Y, Cheng G, Yang H. Acetylation and deacetylation dynamics in stress response to cancer and infections. Semin Immunol 2025; 78:101957. [PMID: 40288003 DOI: 10.1016/j.smim.2025.101957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025]
Abstract
In response to stress stimuli, cells have evolved various mechanisms to integrate internal and external signals to achieve dynamic homeostasis. Lysine acetyltransferase (KATs) and deacetyltransferase (KDACs) are the key modulators of epigenetic modifications, enabling cells to modulate cellular responses through the acetylation and deacetylation of both histone and nonhistone proteins. Understanding the signaling pathways involved in cellular stress response, along with the roles of KATs and KDACs may pave the way for the development of novel therapeutic strategies. This review discusses the molecular mechanisms of acetylation and deacetylation in stress responses related to tumorigenesis, viral and bacterial infections. In tumorigenesis section, we focused on the tumor cells' intrinsic and external molecules and signaling pathways regulated by acetylation and deacetylation modification. In viral and bacterial infections, we summarized the update research on acetylation and deacetylation modification in viral and bacterial infections, which systematical introduction on this topic is not too much. Additionally, we provide an overview of current therapeutic interventions and clinical trials involving KAT and KDAC inhibitors in the treatment of cancer, as well as viral and bacterial infection-related diseases.
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Affiliation(s)
- Lili Li
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Yanqiong Zeng
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China
| | - Genhong Cheng
- Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Heng Yang
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China
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Kabut J, Gorzelak-Magiera A, Gisterek-Grocholska I. New Therapeutic Targets TIGIT, LAG-3 and TIM-3 in the Treatment of Advanced, Non-Small-Cell Lung Cancer. Int J Mol Sci 2025; 26:4096. [PMID: 40362333 PMCID: PMC12072094 DOI: 10.3390/ijms26094096] [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: 03/10/2025] [Revised: 04/20/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
The introduction of immunotherapy and target therapy into clinical practice has become a chance for many patients with cancer to prolong their survival while maintaining optimal quality of life. Treatment of lung cancer is excellent evidence of the progress of medical therapies. An understanding of the mechanisms of tumor development has led to the evolution of new methods of treatment. Immunoreceptors of T cells with the immunoglobulin domain ITIM, TIM-3 (T-cell immunoglobulin- and mucin domain-3-containing molecule 3), and LAG-3 (lymphocyte activation gene-3) represent new interesting therapeutic targets. The combination of anti-PD-1 and anti-CTLA-4 blockade has proven the possibility of strengthening the anti-tumor response by acting via two separate mechanisms. Adding additional checkpoints to the PD-1 blockade offers hope for further improvements in the effects of the treatment of patients and expanding the group responding to immunotherapy. This paper presents new promising molecular targets along with studies demonstrating the treatment results using them.
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Affiliation(s)
- Jacek Kabut
- Department of Oncology and Radiotherapy, Medical University of Silesia, 40-514 Katowice, Poland;
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Wang X, Li S, Fan D, Luo Y, Chen H, Wang Z, Yuan X, Liu J, Wang Z. Metformin induces apoptosis in pituitary-derived folliculostellate cells via the IL-6/ERK pathway. Discov Oncol 2025; 16:598. [PMID: 40268805 PMCID: PMC12018665 DOI: 10.1007/s12672-025-02372-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: 12/30/2024] [Accepted: 04/11/2025] [Indexed: 04/25/2025] Open
Abstract
PURPOSE The aim of this study was to investigate the function and regulatory mechanism of Interleukin-6 (IL-6) in pituitary-derived folliculostellate (PDFS) cells and to explore the mechanism of metformin against PDFS cells growth through IL-6. METHODS Immunohistochemical staining was conducted on clinical samples from non-functioning pituitary adenomas (NFPA) patients and normal individuals to assess IL-6 and Programmed Death-Ligand 1(PD-L1) expression. PDFS cells were treated with IL-6 to evaluate their effects on cell viability, proliferation, and migration through various assays. Similar assays were performed to assess the counteractive effects of metformin, focusing on the IL-6/ERK pathway and PD-L1 expression. Western blot analysis was utilized to examine apoptosis-related proteins, and Annexin V-FITC/PI double staining was used to detect cell apoptosis. It also involves assessing the effects of metformin treatment on tumor IL-6 and PD-L1 expression, tumor size, and potential toxic side effects in PDFS xenograft mice. RESULTS Clinical samples showed increased IL-6 and PD-L1 expression in NFPA compared to normal pituitary tissues. IL-6 treatment significantly enhanced PDFS cell viability(Increased by 46% within 48 h), proliferation(Increased by 24% within 48 h), and migration(Increased by 19% within 48 h). Metformin treatment resulted in the downregulation of IL-6 expression and mitigated IL-6-induced effects on PDFS cells. Additionally, metformin-induced apoptosis and reduced tumor size in xenograft nude mice without observable toxic side effects. CONCLUSION Metformin downregulates the expression of IL-6 in PDFS cells, inhibits the activation of the ERK pathway, thereby suppressing cell proliferation and PD-L1 expression, and induces cell apoptosis.
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Affiliation(s)
- Xin Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Siyuan Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Dong Fan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Yuyou Luo
- Guangzhou Huaxia Vocational College, Guangzhou, 510935, Guangdong, China
| | - Huitong Chen
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Zhongyu Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Xingyi Yuan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Jing Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
| | - Zongming Wang
- Department of Neurosurgery, Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.
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Carneiro HC, Natal RDA, Vassallo J, Soares FA. PD-L1 and FOXP3 expression in high-grade squamous intraepithelial lesions of the anogenital region. Oncotarget 2025; 16:277-290. [PMID: 40270290 PMCID: PMC12060918 DOI: 10.18632/oncotarget.28715] [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: 08/26/2024] [Accepted: 04/17/2025] [Indexed: 04/25/2025] Open
Abstract
Host immunosurveillance is an important factor in the progression of high-grade squamous intraepithelial lesions (HSIL) into high-risk human papillomavirus (HR-HPV)-related squamous cell carcinoma. Immune escape by forkhead box protein P3 (FOXP3+) immunoregulatory T cells and the programmed death-ligand 1 (PD1/PD-L1) axis, mechanisms best described in the context of invasive neoplasms, may play a role in the evolution of pre-malignant lesions. This morphological study aimed to characterize the inflammatory response and expression of FOXP3 and PD-L1 in anal, vulvar, and penile HSILs and compare them with those in low-grade SILs co-infected with HR-HPV (LSILHR). The study group comprised 157 samples from 95 male and 55 female patients (median age = 35.5 years), including 122 HSILs and 35 LSILsHR. Dense inflammatory infiltrates and high counts of FOXP3+ cells were significantly more frequent in patients with HSILs than in those with LSILsHR (p = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression (padj < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model. In addition, concordant higher PD-L1 expression was observed in cases with a greater number of FOXP3+ cells (p < 0.05). Our findings indicate a putative role of transcriptionally active HR-HPV in evoking an inflammatory response and immune evasion in the early phases of carcinogenesis in a subset of non-cervical anogenital HSILs.
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Affiliation(s)
- Humberto Carvalho Carneiro
- Instituto D’Or de Pesquisa e Ensino (IDOR), São Paulo 04501-000, Brazil
- Department of Anatomic Pathology, Rede D’Or, São Paulo 04321-120, Brazil
| | - Rodrigo de Andrade Natal
- Instituto D’Or de Pesquisa e Ensino (IDOR), São Paulo 04501-000, Brazil
- Department of Anatomic Pathology, Rede D’Or, São Paulo 04321-120, Brazil
| | - José Vassallo
- Instituto D’Or de Pesquisa e Ensino (IDOR), São Paulo 04501-000, Brazil
- Department of Anatomic Pathology, Rede D’Or, São Paulo 04321-120, Brazil
| | - Fernando Augusto Soares
- Instituto D’Or de Pesquisa e Ensino (IDOR), São Paulo 04501-000, Brazil
- Department of Anatomic Pathology, Rede D’Or, São Paulo 04321-120, Brazil
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Babayev P, Ismayilov R, Kuscu O, Akyildiz A, Kurtulan O, Pamuk E, Guler Tezel YG, Gullu IH. Does high PD-L1 expression reduce the risk of relapse after definitive surgery in patients with oral cavity cancer? Acta Otolaryngol 2025:1-6. [PMID: 40266268 DOI: 10.1080/00016489.2025.2489645] [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: 03/07/2025] [Accepted: 04/01/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND Uncovering the molecular mechanisms of cancer pathogenesis is crucial for improving survival outcomes. AIMS This study investigates the impact of programmed death ligand 1 (PD-L1) expression on the risk of progression in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS The retrospective study included adult patients diagnosed with OSCC between January 2012 and December 2023. PD-L1 expression in tissue removed by definitive surgery was evaluated using immunohistochemistry, and tumor proportion score (TPS) and combined positive score (CPS) were calculated. Survival analyses were performed to assess its prognostic implications. RESULTS Among the 96 patients, TPS and CPS were 20% or above in 52 (54.2%) and 65 (67.7%) cases, respectively. TPS ≥20% was associated with mucosal lip location, earlier disease stage, and decreased risk of progression. The multivariate Cox regression model revealed that stage III/IV disease (HR: 2.176, 95%CI: 1.085-4.376, p = .029) and TPS ≥20% (HR: 0.241, 95%CI: 0.066-0.879, p = .031) were independent risk factors for progression-free survival. CONCLUSIONS The study revealed that increased tumoral PD-L1 expression may reduce the risk of progression in patients with OSCC. SIGNIFICANCE These findings underscore the potential prognostic significance of PD-L1 expression in OSCC following surgical resection.
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Affiliation(s)
- Parvin Babayev
- Department of Otorhinolaryngology, Hacettepe University Medical School, Ankara, Turkey
| | - Rashad Ismayilov
- Department of Internal Medicine, Hacettepe University Medical School, Ankara, Turkey
| | - Oguz Kuscu
- Department of Otorhinolaryngology, Hacettepe University Medical School, Ankara, Turkey
| | - Arif Akyildiz
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Olcay Kurtulan
- Department of Pathology, Hacettepe University Medical School, Ankara, Turkey
| | - Erim Pamuk
- Department of Otorhinolaryngology, Hacettepe University Medical School, Ankara, Turkey
| | | | - Ibrahim Halil Gullu
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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Ren J, Yan G, Yang L, Kong L, Guan Y, Sun H, Liu C, Liu L, Han Y, Wang X. Cancer chemoprevention: signaling pathways and strategic approaches. Signal Transduct Target Ther 2025; 10:113. [PMID: 40246868 PMCID: PMC12006474 DOI: 10.1038/s41392-025-02167-1] [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: 08/02/2024] [Revised: 12/01/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025] Open
Abstract
Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.
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Affiliation(s)
- Junling Ren
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Guangli Yan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China
| | - Ling Kong
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Yu Guan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Hui Sun
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Chang Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Lei Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Ying Han
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Xijun Wang
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China.
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Hetta HF, Aljohani HM, Sirag N, Elfadil H, Salama A, Al-Twalhy R, Alanazi D, Al-johani MD, Albalawi JH, Al-Otaibi RM, Alsharif RA, Sayad R. Synergizing Success: The Role of Anlotinib Combinations in Advanced Non-Small Cell Lung Cancer Treatment. Pharmaceuticals (Basel) 2025; 18:585. [PMID: 40284020 PMCID: PMC12030542 DOI: 10.3390/ph18040585] [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: 02/24/2025] [Revised: 04/08/2025] [Accepted: 04/13/2025] [Indexed: 04/29/2025] Open
Abstract
Anlotinib, a novel receptor tyrosine kinase inhibitor that is taken orally, targets several RTKs and is authorized as a third-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Anlotinib is also used in combination with immunotherapy or chemotherapy for advanced NSCLC. We aimed to explore the efficacy and safety of anlotinib-based regimens in NSCLC treatment, focusing on combination therapies. We also addressed challenges that hinder oncologists from using it, such as toxicity and resistance mechanisms. A systematic approach involves searching the National Institute of Health PubMed, Scopus, MedLine, and Web of Science databases up to April 2024. Relevant studies were identified and analyzed for their methodologies, outcomes, and patient characteristics. Findings revealed that numerous effective combination regimens, such as anlotinib with platinum-based chemotherapy and anlotinib combined with PD-1 blockades, have shown positive results in terms of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). On the other hand, NSCLC treatment faces hurdles due to drug resistance and its toxicity profile. These challenges underscore the need for continued research and optimization of treatment strategies.
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Affiliation(s)
- Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Hashim M. Aljohani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madina 41477, Saudi Arabia;
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Nizar Sirag
- Division of Pharmacognosy, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Hassabelrasoul Elfadil
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Ayman Salama
- Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Rand Al-Twalhy
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Danah Alanazi
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Manal D. Al-johani
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Jumanah H. Albalawi
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Rinad M. Al-Otaibi
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Raghad A. Alsharif
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.-T.); (D.A.); (M.D.A.-j.); (J.H.A.); (R.M.A.-O.); (R.A.A.)
| | - Reem Sayad
- Department of Histology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
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Zhang L, Lin H, Liang J, Liu X, Zhang C, Man Q, Li R, Zhao Y, Liu B. Programmed death-ligand 1 regulates ameloblastoma growth and recurrence. Int J Oral Sci 2025; 17:29. [PMID: 40240323 PMCID: PMC12003687 DOI: 10.1038/s41368-025-00364-w] [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: 09/22/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 04/18/2025] Open
Abstract
Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate tumor initiation, progression and metastasis, but their effects in ameloblastoma (AM) have not been reported. In this comprehensive study, we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates. Notably, we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT+-AM cells, whereas genetic ablation of PD-L1 exerted opposing inhibitory effects. By performing high-resolution single-cell profiling and thorough immunohistochemical analyses in AM patients, we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors. Our findings revealed that hTERT+-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial‒mesenchymal transition. This phenotypic shift is induced by the activation of the PI3K-AKT-mTOR signaling axis; thus, this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence. Importantly, targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patient-derived tumor organoids, highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.
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Affiliation(s)
- Linzhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hao Lin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jiajie Liang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xuanhao Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Chenxi Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Qiwen Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ruifang Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yi Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Prosthodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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40
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Zhang G, Zhang G, Zhao Y, Wan Y, Jiang B, Wang H. Unveiling the nexus of p53 and PD-L1: insights into immunotherapy resistance mechanisms in hepatocellular carcinoma. Am J Cancer Res 2025; 15:1410-1435. [PMID: 40371157 PMCID: PMC12070102 DOI: 10.62347/brto3272] [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: 01/26/2025] [Accepted: 03/25/2025] [Indexed: 05/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer worldwide, continues to pose a substantial health challenge with limited treatment options for advanced stages. Despite progress in therapies such as surgery, transplantation, and targeted treatments, prognosis remains bleak for many patients. The advent of immunotherapy has revolutionized the landscape of advanced HCC treatment, offering hope for improved outcomes. However, its efficacy is limited, with a modest response rate of approximately 20% as a single-agent therapy, underscoring the urgent need to decipher mechanisms of immunotherapy resistance. Tumor protein 53 gene (TP53), a pivotal tumor suppressor gene, and Programmed death ligand 1 (PD-L1), a crucial immune checkpoint ligand, play central roles in HCC's evasion of immune responses. Understanding how tumor protein 53 (p53) influences PD-L1 expression and immune system interactions is essential for unraveling the complexities of immunotherapy resistance mechanisms. Elucidating these molecular interactions not only enhances our understanding of HCC's underlying mechanisms but also lays the foundation for developing targeted treatments that may improve outcomes for patients with advanced-stage liver cancer. Ultimately, deciphering the nexus of p53 and PD-L1 in immunotherapy resistance promises to advance treatment strategies and outcomes in the challenging landscape of HCC. This review delves into the intricate relationship between p53 and PD-L1 concerning immunotherapy resistance in HCC, offering insights that could pave the way for novel therapeutic strategies aimed at enhancing treatment efficacy and overcoming resistance in advanced stages of the disease.
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Affiliation(s)
- Guoyuan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Gan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Yixuan Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Yunyan Wan
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Bin Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Huaxiang Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
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Da Z, Yang H, Zhaxi B, Sun K, Bai G, Wang C, Wang F, Pan W, Du R. Multiple instance learning-based prediction of programmed death-ligand 1 (PD-L1) expression from hematoxylin and eosin (H&E)-stained histopathological images in breast cancer. PeerJ 2025; 13:e19201. [PMID: 40256728 PMCID: PMC12007500 DOI: 10.7717/peerj.19201] [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: 12/16/2024] [Accepted: 03/03/2025] [Indexed: 04/22/2025] Open
Abstract
Programmed death-ligand 1 (PD-L1) is an important biomarker increasingly used as a predictive marker in breast cancer immunotherapy. Immunohistochemical quantification remains the standard method for assessment. However, it presents challenges related to time, cost, and reliability. Hematoxylin and eosin (H&E) staining is a routine method in cancer pathology, known for its accessibility and consistently reliability. Deep learning has shown the potential in predicting biomarkers in cancer histopathology. This study employs a weakly supervised multiple instance learning (MIL) approach to predict PD-L1 expression from H&E-stained images using deep learning techniques. In the internal test set, the TransMIL method achieved an area under the curve (AUC) of 0.833, and in an independent external test set, it achieved an AUC of 0.799. Additionally, since RNA sequencing results indicate a threshold that allows for the separation of H&E pathology images, we further validated our approach using the public TCGA-TNBC dataset, achieving an AUC of 0.721. These findings demonstrates that the Transformer-based TransMIL model can effectively capture highly heterogeneous features within the MIL framework, exhibiting strong cross-center generalization capabilities. Our study highlights that appropriate deep learning techniques can enable effective PD-L1 prediction even with limited data, and across diverse regions and centers. This not only underscores the significant potential of deep learning in pathological artificial intelligence (AI) but also provides valuable insights for the rational and efficient allocation of medical resources.
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Affiliation(s)
- Zhen Da
- Department of Pathology, People’s Hospital of Xizang Autonomous Region, Lhasa, Xizang, China
- Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Heng Yang
- Kunyuan Fangqing Medical Technology Co., LTD, Guangzhou, Guangdong, China
- Jinfeng Laboratory, Chongqing, China
| | - Bianba Zhaxi
- Department of General Surgery, People’s Hospital of Xizang Autonomous Region, Lhasa, Xizang, China
| | - Kaixiang Sun
- Kunyuan Fangqing Medical Technology Co., LTD, Guangzhou, Guangdong, China
- Jinfeng Laboratory, Chongqing, China
| | - Guohui Bai
- Department of General Surgery, People’s Hospital of Xizang Autonomous Region, Lhasa, Xizang, China
| | - Chao Wang
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangzhou, Guangdong, China
| | - Feiyan Wang
- Kunyuan Fangqing Medical Technology Co., LTD, Guangzhou, Guangdong, China
- Jinfeng Laboratory, Chongqing, China
| | - Weijun Pan
- Jinfeng Laboratory, Chongqing, China
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangzhou, Guangdong, China
| | - Rui Du
- Department of Pathology, People’s Hospital of Xizang Autonomous Region, Lhasa, Xizang, China
- Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
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Li J, Wang A, Guo H, Zheng W, Chen R, Miao C, Zheng D, Peng J, Wang J, Chen Z. Exosomes: innovative biomarkers leading the charge in non-invasive cancer diagnostics. Theranostics 2025; 15:5277-5311. [PMID: 40303340 PMCID: PMC12036879 DOI: 10.7150/thno.113650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 04/06/2025] [Indexed: 05/02/2025] Open
Abstract
Exosomes, nanoscale extracellular vesicles secreted by diverse cell types, have emerged as promising biomarkers for non-invasive tumor diagnostics, offering significant advantages over traditional methods. These vesicles, typically ranging from 30 to 150 nanometers in size, carry a diverse cargo of proteins, lipids, RNA, and microRNAs, which reflect the molecular alterations occurring within their parent cells. Notably, exosomes can be isolated from easily accessible biofluids such as blood, urine, and saliva, making them ideal candidates for liquid biopsy applications. This review explores the transformative potential of exosome-based biomarkers in the early detection and monitoring of cancers across diverse organ systems, including respiratory, digestive, hematological, neurological, endocrine malignancies and so on. Special emphasis is placed on their application in clinical trials, where exosome-based diagnostics have demonstrated promising results in detecting tumors at early stages and monitoring treatment responses, offering a less invasive and more accessible alternative to traditional biopsies. While recent advancements in exosome isolation and characterization technologies have significantly improved the sensitivity and specificity of these diagnostics, challenges such as biological heterogeneity, lack of standardization, and regulatory hurdles remain. Nevertheless, exosome-based diagnostics hold the promise of providing real-time, dynamic insights into tumor progression, enhancing personalized medicine. The integration of exosomes into clinical practice could revolutionize cancer diagnostics and therapy, improving patient outcomes. Further research and large-scale clinical validation are essential to fully realize the clinical potential of exosome-based biomarker applications in routine clinical settings.
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Affiliation(s)
- Jiale Li
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China, 570208
| | - Ailin Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China, 211198
| | - Haijun Guo
- Department of Neurosurgery, Central Hospital of Zhuzhou, Zhuzhou, Hunan, China, 412000
| | - Wei Zheng
- Department of Neurosurgery, Central Hospital of Zhuzhou, Zhuzhou, Hunan, China, 412000
| | - Rui Chen
- Department of Neurosurgery, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China, 533000
| | - Changfeng Miao
- Department of Neurosurgery Second Branche, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, China, 410005
| | - Dandan Zheng
- Department of Radiation Oncology, The First Affiliated Hospital Zhejiang University, Hangzhou, China, 310009
| | - Jun Peng
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China, 570208
| | - Jiachong Wang
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China, 570208
| | - Zigui Chen
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China, 570208
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43
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Tarin M, Oryani MA, Javid H, Karimi-Shahri M. Exosomal PD-L1 in non-small cell lung Cancer: Implications for immune evasion and resistance to immunotherapy. Int Immunopharmacol 2025; 155:114519. [PMID: 40199140 DOI: 10.1016/j.intimp.2025.114519] [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: 11/05/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/10/2025]
Abstract
Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.
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Affiliation(s)
- Mojtaba Tarin
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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44
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Tang L, Hu Y, Wang C, Han W, Wang P. Analysis of mutually exclusive expression in cancer cells identifies a previously unknown intergenic regulatory paradigm. FEBS J 2025. [PMID: 40186387 DOI: 10.1111/febs.70089] [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: 09/02/2024] [Revised: 01/31/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Mutual exclusion of gene expression has received limited attention. Gene (expression) plasticity analysis provides an efficient way to identify highly plastic genes (HPGs) based on changes in expression rank. In this study, we quantitatively measured the expression plasticity of 19 961 protein-coding genes in 24 human cancer cell lines and identified HPGs in these cells. By comparing methods, we showed that virtual sorting and cosine similarity, rather than Pearson and Spearman rank correlations, are suitable for mutual exclusion. Mutually exclusive gene pairs were identified in each cell type. Experimental validation showed that thiol methyltransferase 1B (TMT1B; also known as METTL7B) and CD274 molecule (CD274; also known as PD-L1) were mutually exclusively expressed at either the mRNA or protein level. METTL7B negatively regulated PD-L1 expression in several cell types, and the JAK/STAT3 pathway was involved. Knockdown of METTL7B in Huh7 cells inhibited interleukin 2 (IL-2) secretion by Jurkat cells in co-culture experiments, and the inhibition was blocked by anti-PD-L1 antibodies. Therefore, this study provides an efficient method of expressional mutual exclusion and implies a newly identified intergenic regulatory paradigm.
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Affiliation(s)
- Ling Tang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuzhe Hu
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
| | - Chao Wang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
| | - Wenling Han
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
| | - Pingzhang Wang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
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45
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Gao Y, Nie HQ, Liu HM, Zhang XH, Ma LY. Rational Design, Synthesis, and Biological Assessment of Potential Indole-Capped HDAC6 Inhibitors for Gastric Cancer Suppression. MedComm (Beijing) 2025; 6:e70158. [PMID: 40115907 PMCID: PMC11923385 DOI: 10.1002/mco2.70158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 02/23/2025] [Accepted: 02/24/2025] [Indexed: 03/23/2025] Open
Affiliation(s)
- Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences Zhengzhou University Zhengzhou Henan China
| | - Hai-Qian Nie
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences Zhengzhou University Zhengzhou Henan China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences Zhengzhou University Zhengzhou Henan China
| | - Xin-Hui Zhang
- School of Biological Engineering Henan University of Technology Zhengzhou Henan China
| | - Li-Ying Ma
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences Zhengzhou University Zhengzhou Henan China
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46
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Lu X, Jin P, Tang Q, Zhou M, Xu H, Su C, Wang L, Xu F, Zhao M, Yin Y, Zhang J, Jia Z, Peng X, Zhou J, Wang L, Chen Y, Wang M, Yang M, Chen D, Chen Y. NAD + Metabolism Reprogramming Drives SIRT1-Dependent Deacetylation Inducing PD-L1 Nuclear Localization in Cervical Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412109. [PMID: 39988985 PMCID: PMC12005810 DOI: 10.1002/advs.202412109] [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: 09/29/2024] [Revised: 01/23/2025] [Indexed: 02/25/2025]
Abstract
Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD+) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.
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Affiliation(s)
- Xinyi Lu
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
- Wuxi Medical CenterNanjing Medical UniversityJiangsu214023China
| | - Pingping Jin
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Qianyun Tang
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Min Zhou
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Hanjie Xu
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Chen Su
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Lei Wang
- Wuxi Medical CenterNanjing Medical UniversityJiangsu214023China
- Department of Hepatopancreatobiliary SurgeryJiangnan University Medical CenterJiangsu214002China
| | - Feng Xu
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Min Zhao
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Yongxiang Yin
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Jinqiu Zhang
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Zhen Jia
- Department of LaboratoryHaidong Second People's HospitalHaidong810699China
| | - Xinrui Peng
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Jie Zhou
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Lu Wang
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Yan Chen
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
| | - Min Wang
- Wuxi Medical CenterNanjing Medical UniversityJiangsu214023China
| | - Min Yang
- Molecular Imaging CentreJiangsu Institute of Nuclear MedicineJiangsu214063China
| | - Daozhen Chen
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
- Wuxi Medical CenterNanjing Medical UniversityJiangsu214023China
- Department of LaboratoryHaidong Second People's HospitalHaidong810699China
| | - Yu Chen
- Affiliated Women's Hospital of Jiangnan UniversityJiangnan UniversityJiangsu214002China
- Wuxi Medical CenterNanjing Medical UniversityJiangsu214023China
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Chevaleyre C, Zimmermann L, Specklin S, Kereselidze D, Bouleau A, Dubois S, Quelquejay H, Maillère B, Tournier N, Nozach H, Truillet C. PET Imaging of PD-L1 Occupancy for Preclinical Assessment of the Efficacy of Combined Anti-PD-L1 Immunotherapy and Targeted Therapy. J Nucl Med 2025; 66:559-564. [PMID: 39978814 DOI: 10.2967/jnumed.124.268586] [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: 08/09/2024] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
The development of resistance significantly hampers the efficacy of immunotherapies in cancer treatment. The combination of JQ1, a BRD4 protein inhibitor, and anti-programmed death ligand 1 (PD-L1) immunotherapies has a synergic therapeutic potential to treat solid tumors. This study aimed to evaluate the potential of immuno-PET imaging for measuring pharmacodynamic biomarkers in response to this combination therapy targeting PD-L1. Methods: We synthesized different radioligands derived from the anti-PD-L1 C4 antibody and a minibody targeting murine CD8α for immuno-PET imaging. We conducted experiments on human non-small cell lung cancer and mouse colorectal carcinoma animal models to assess the efficacy of JQ1 and avelumab treatment on PD-L1 expression and immune cell infiltration by immuno-PET imaging. Taking advantage of the unique properties of the C4-derived minibody, we measured PD-L1 occupancy in tumors after treatment. Results: JQ1 efficiently reduced PD-L1 extracellular expression across all tested cell lines in vitro and in vivo. Avelumab and JQ1 treatments alone or in combination led to significant tumor growth reduction in the immunocompetent murine colorectal carcinoma model, reducing mean tumor growth from 725% in the control group to 125% in the combination group. Treatments also significantly increased the survival of mice by 4-12 d compared with the control group. Although imaging CD8-positive T-cell infiltration did not predict tumoral response, imaging the unoccupied fraction of PD-L1 after treatment was predictive of tumor growth reduction and survival. Conclusion: Immuno-PET imaging with noncompetitive radioligands throughout the treatment course could improve the efficiency and support rationalization of the dosing regimen of immunotherapies.
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Affiliation(s)
- Céline Chevaleyre
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Léa Zimmermann
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Simon Specklin
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Dimitri Kereselidze
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Alizée Bouleau
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Steven Dubois
- SIMoS, Healthcare Technologies Department, INRAE, CEA, Paris-Saclay University, Gif-sur-Yvette, France
| | - Hélène Quelquejay
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Bernard Maillère
- SIMoS, Healthcare Technologies Department, INRAE, CEA, Paris-Saclay University, Gif-sur-Yvette, France
| | - Nicolas Tournier
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
| | - Hervé Nozach
- SIMoS, Healthcare Technologies Department, INRAE, CEA, Paris-Saclay University, Gif-sur-Yvette, France
| | - Charles Truillet
- BioMaps, Service Hospitalier Frédéric Joliot, INSERM, CNRS, CEA, Paris-Saclay University, Orsay, France; and
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48
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Alghazali T, Ahmed AT, Hussein UAR, Sanghvi G, Uthirapathy S, Edan RT, Lal M, Shit D, Naidu KS, Al-Hamairy AK. Noncoding RNA (ncRNA)-mediated regulation of TLRs: critical regulator of inflammation in tumor microenvironment. Med Oncol 2025; 42:144. [PMID: 40163200 DOI: 10.1007/s12032-025-02690-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
Toll-like receptors (TLRs) are central components of the innate immune system as they recognize molecular patterns associated with pathogens and cellular damage and initiate immune responses using MyD88- and TRIF-dependent pathways. In contrast to being very useful for immune defense, dysregulated TLR signaling may be involved in diseases, such as cancer and autoimmune conditions. In cancer, TLRs create an environment that supports tumorigenesis and growth. In addition to this, a class of multifunctional noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, regulate gene expression without encoding proteins. MiRNAs regulate gene expression in a fine-tuned manner, while lncRNAs and circRNAs do so via diverse mechanisms. Notably, these ncRNAs interact, where lncRNAs and circRNAs function as competing endogenous RNAs and ceRNA, affecting miRNA activity. This interaction has a vital role in cancer pathology, in influencing that of various oncogenes and tumor suppressors in the tumor microenvironment; hence, modulation of ncRNAs could also be a great promising therapeutic approach. In this context, interplay between TLRs and ncRNAs is of paramount importance as they influence various parameters of the tumor microenvironment. TLR signaling works upon the expression of ncRNAs, while ncRNAs work back to regulate TLR signaling in return. An example of this includes miRNA targeting of components of the TLR; lncRNAs induced by TLR signaling possibly would favor tumor progression. Pharmacological interventions directed toward inhibiting these TLR pathways could be the model to halt malignancy by hampering pro-tumor inflammation and boosting immune responses against neoplasms. Hence, the review will highlight the complicated contrast of ncRNAs and TLRs within human cancer. By connecting the mechanisms, the researchers may study more about tumorigenesis and gather up new, innovative notions regarding therapeutic targeting.
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Affiliation(s)
| | | | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Reem Turki Edan
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Madan Lal
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Debasish Shit
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Ahmed Khudhair Al-Hamairy
- Anesthesia Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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49
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Wang Y, Zhang M, Zhang T, Zhang S, Ji F, Qin J, Li H, Jiao J. PD-L1/PD-1 checkpoint pathway regulates astrocyte morphogenesis and myelination during brain development. Mol Psychiatry 2025:10.1038/s41380-025-02969-3. [PMID: 40164696 DOI: 10.1038/s41380-025-02969-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/05/2025] [Accepted: 03/20/2025] [Indexed: 04/02/2025]
Abstract
Programmed cell death protein 1 (PD-1) and its primary ligand PD-L1 are integral components of a significant immune checkpoint pathway, widely recognized for its central role in cancer immunotherapy. However, emerging evidence highlights their broader involvement in both the central and peripheral nervous systems. In this study, we demonstrate that PD-L1/PD-1 signaling in astrocytes during mouse brain development regulates astrocyte maturation and morphogenesis via the MEK/ERK pathway by targeting the downstream effector cysteine and glycine rich protein 1 (CSRP1). This enhanced astrocyte morphological complexity results in increased end-foot coverage of blood vessels. Additionally, aberrant secretion of CSRP1 by astrocytes interacts with oligodendrocyte precursor cells (OPCs) membrane proteins annexin A1 (ANXA1) and annexin A2 (ANXA2), leading to the exclusion of migrating OPCs from blood vessels. This disruption in OPC migration and differentiation results in abnormal myelination and is associated with cognitive deficits in the mice. Our results provide critical insights into the function of PD-L1/PD-1 signaling in astrocyte-OPC interactions and underscore its relevance to glial cell development and pathogenesis in neurodevelopmental disorders.
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Affiliation(s)
- Yanyan Wang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Mengtian Zhang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Tianyu Zhang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shukui Zhang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fen Ji
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jie Qin
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hong Li
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianwei Jiao
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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50
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Shi Z, Hu C, Li Q, Sun C. Cancer-Associated Fibroblasts as the "Architect" of the Lung Cancer Immune Microenvironment: Multidimensional Roles and Synergistic Regulation with Radiotherapy. Int J Mol Sci 2025; 26:3234. [PMID: 40244052 PMCID: PMC11989671 DOI: 10.3390/ijms26073234] [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: 02/19/2025] [Revised: 03/20/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs), as the "architect" of the immune microenvironment in lung cancer, play a multidimensional role in tumor progression and immune regulation. In this review, we summarize the heterogeneity of the origin and the molecular phenotype of CAFs in lung cancer, and explore the complex interactions between CAFs and multiple components of the tumor microenvironment, including the regulatory relationships with innate immune cells (e.g., tumor-associated macrophages, tumor-associated neutrophils), adaptive immune cells (e.g., T cells), and extracellular matrix (ECM). CAFs significantly influence tumor progression and immunomodulation through the secretion of cytokines, remodeling of the ECM, and the regulation of immune cell function significantly affects the immune escape and treatment resistance of tumors. In addition, this review also deeply explored the synergistic regulatory relationship between CAF and radiotherapy, revealing the key role of CAF in radiotherapy-induced remodeling of the immune microenvironment, which provides a new perspective for optimizing the comprehensive treatment strategy of lung cancer. By comprehensively analyzing the multidimensional roles of CAF and its interaction with radiotherapy, this review aims to provide a theoretical basis for the precise regulation of the immune microenvironment and clinical treatment of lung cancer.
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Affiliation(s)
- Zheng Shi
- School of Biopharmaceutical and Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (C.H.); (Q.L.); (C.S.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Cuilan Hu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (C.H.); (Q.L.); (C.S.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (C.H.); (Q.L.); (C.S.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (C.H.); (Q.L.); (C.S.)
- University of Chinese Academy of Sciences, Beijing 101408, China
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