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Cai C, Zhang Q, Ye J, Yao S, Li Q, Fan Z, Ge S, Wang Y, Xu D, Zhou J, Cheng H, Ding Y. Tumor microenvironment modulation innovates combinative cancer therapy via a versatile graphene oxide nanosystem. Biomater Sci 2025; 13:3123-3148. [PMID: 40314424 DOI: 10.1039/d5bm00202h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
The tumor microenvironment (TME) emerges as a unique challenge to oncotherapy due to its intricate ecosystem containing diverse cell types, extracellular matrix, secreted factors, and neovascularization, which furnish tumor growth, progression, invasion, and metastasis. Graphene oxide (GO)-based materials have garnered increasing attention in cancer therapy owing to their vast specific surface area, flexible lamellar structure, and electronic-photonic properties. Recently, interactions of GO with the TME have been broadly investigated, including trapping biomolecules, catalysis, cancer stem cell targeting, immunoreactions, etc., which inspires combinative therapeutic strategies to overcome TME obstacles. Herein, we summarize TME features, GO modulating various dimensions of the TME, and a TME-triggerable drug delivery system and highlight innovation and merits in combinative cancer therapy based on TME modulation. This review aims to offer researchers deeper insights into the interactions between versatile GO nanomaterials and the TME, facilitating the development of rational and reliable GO-based nanomedicines for advanced oncotherapy.
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Affiliation(s)
- Chuxin Cai
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Qingming Zhang
- Department of Pharmacy, Jinling Hospital, No. 305 East Zhongshan Road, Nanjing 210002, Jiangsu, People's Republic of China
| | - Junqiu Ye
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Sijia Yao
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Qian Li
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Zhechen Fan
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Sulei Ge
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Yukun Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Dingyi Xu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Jianping Zhou
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Cheng
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Yang Ding
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
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Guan H, Tao H, Luo J, Wan L, Hu H, Chen L, Wen Z, Tao Y, Chen S, Gu M. Upregulation of YY1 in M2 macrophages promotes secretion of exosomes containing hsa-circ-0000326 via super-enhancers to facilitate prostate cancer progression. Mol Cell Biochem 2025; 480:3873-3888. [PMID: 39960585 DOI: 10.1007/s11010-025-05222-1] [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: 11/02/2024] [Accepted: 01/30/2025] [Indexed: 05/23/2025]
Abstract
The transcription factor YY1 is significantly upregulated in M2 macrophages, which can facilitate the malignant progression of multiple cancers. However, the precise mechanisms underlying the influence of YY1-high M2 macrophages on prostate cancer (PCa) progression remain elusive. Therefore, this study aims to elucidate the specific mechanisms by which YY1-high M2 macrophages influence PCa progression. Cell proliferation was assessed through colony formation and CCK8 assays. To evaluate cell invasion and migration, Transwell and wound healing assays were utilized. We investigated the effects of exosomes derived from M2 macrophages overexpressing YY1 on PCa cells. Subsequently, circRNA microarrays and qRT-PCR identified a high level of hsa-circ-0000326 in exosomes. Nucleoplasmic isolation, luciferase reporter, RNA-pulldown assays elucidated the functions and downstream targets (miR-338-3p and AR) of hsa-circ-0000326. Chromatin immunoprecipitation sequencing, chromatin conformation capture, qRT-PCR, western blotting, and agarose-electrophoresis assays examined YY1's role in transcribing the hsa-circ-0000326 maternal gene MALAT1 as well as its modulation of QKI expression. Our results demonstrated that the secretion of exosomes enriched with hsa-circ-0000326 by YY1-overexpressing M2 macrophages contributes to PCa metastasis. Hsa-circ-0000326 functions as a competitive endogenous RNA against miR-338-3p to promote androgen receptor levels in PCa cells. Mechanistic investigations revealed that YY1 binds to the super-enhancer region of MALAT1 enhancing transcriptional activity for this gene. Simultaneously, YY1 upregulates QKI expression, facilitating splicing events leading to the formation of hsa-circ-0000326. Inhibiting exosomal hsa-circ-0000326 presents a potential therapeutic approach for treating metastatic PCa.
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Affiliation(s)
- Han Guan
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Huaixiang Tao
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Jinguang Luo
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Lilin Wan
- Southeast University, Nanjing, China
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Hao Hu
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Long Chen
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Zhiyuan Wen
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Yuxuan Tao
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Saisai Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Mingli Gu
- Department of Urology, The Second Affiliated Hospital of Bengbu Medical University, No. 633 Longhua Road, Huaishang District, Bengbu, 233000, Anhui, China.
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Simon AG, Lyu SI, Schultheis AM, Stahl D, Wuerdemann N, Walter S, Hieggelke L, Buettner R, Bruns CJ, Eysel P, Schiffmann LM, Knipper K, Mallmann P, Quaas A, Ullrich R. Exploration of histone protein γ-H2AX as a prognostic factor in soft tissue sarcomas and its association with biological behavior, immune cell environment and survival in leiomyosarcoma. Int J Cancer 2025; 156:2237-2250. [PMID: 39707602 PMCID: PMC11970547 DOI: 10.1002/ijc.35310] [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: 06/19/2024] [Revised: 12/03/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024]
Abstract
This study evaluates the H2AX/γ-H2AX expression in soft tissue sarcomas (STS), its implications for biological behavior and immune environment, and its potential as a prognostic biomarker. RNA-Seq data from 237 STS were obtained from The Cancer Genome Atlas project. Patients were stratified by H2AX mRNA expression using a survival-associated cutoff. Differentially expressed genes and pathways as well as immune signatures between H2AXhigh- and H2AXlow tumors were identified with DESeq2 analysis, gene set enrichment analyses (GSEA), Enrichr pathway analysis and CIBERSORTx. Tissue microarrays of a different cohort of 291 STS were generated for immunohistochemical staining to assess γ-H2AX protein expression, followed by statistical evaluation. High H2AX mRNA expression was associated with shorter overall survival (OS) in STS (p = 0.02), particularly in leiomyosarcomas (LMS) (p < 0.001), and was a negative prognostic factor in LMS (HR 11.15, p < 0.001). H2AXhigh LMS tumors showed upregulation of cell cycle-related pathways, while H2AXlow LMS exhibited increased inflammatory activity, including elevated M1 macrophage signatures and resting mast cell signatures (both p < 0.001). High γ-H2AX protein levels were an independent negative prognostic factor in the total LMS cohort (HR 12.12, p = 0.025) and in the subgroup of non-uterine LMS (HR 153.80, p = 0.013). Consistent with CIBERSORTx analysis, γ-H2AXlow LMS showed higher mast cell infiltration than γ-H2AXhigh LMS (p = 0.038). In conclusion, H2AX mRNA and γ-H2AX protein expression are associated with distinct biological behavior, differences in the immune cell environment, and might serve as useful prognostic biomarkers in LMS.
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Affiliation(s)
- Adrian Georg Simon
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Su Ir Lyu
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Anne Maria Schultheis
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
- Institute for Surgical Pathology, Medical Center‐University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburg im BreisgauGermany
| | - David Stahl
- Department I of Internal Medicine/Centre for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Nora Wuerdemann
- Department I of Internal Medicine/Centre for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Sebastian Walter
- Department for Orthopedics and Trauma Surgery, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Lena Hieggelke
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Christiane Josephine Bruns
- Department of General, Visceral and Cancer and Transplant Surgery, University Hospital of Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Peer Eysel
- Department for Orthopedics and Trauma Surgery, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Lars Mortimer Schiffmann
- Department of General, Visceral and Cancer and Transplant Surgery, University Hospital of Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Karl Knipper
- Department of General, Visceral and Cancer and Transplant Surgery, University Hospital of Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Peter Mallmann
- Department of Obstetrics and Gynecology, University Hospital of Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
| | - Roland Ullrich
- Department I of Internal Medicine/Centre for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Faculty of MedicineUniversity of CologneCologneGermany
- Centre for Molecular MedicineUniversity of CologneCologneGermany
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Zhou M, Zhang Y, Song W. Single-cell transcriptome analysis identifies subclusters and signature with N-glycosylation in endometrial cancer. Clin Transl Oncol 2025; 27:2467-2483. [PMID: 39589706 DOI: 10.1007/s12094-024-03802-z] [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: 10/08/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Endometrial cancer (EC) is a prevalent gynecologic cancer, with worldwide increasing incidence and disease-associated mortality. N-glycosylation, a critical post-translational modification, has been implicated in cancer progression and immune response modulation. We aimed to elucidate the role of N-glycosylation-related genes on EC cell heterogeneity, prognosis, and immunotherapy response. METHODS Data from single-cell RNA sequencing (scRNA) of five patients with EC were acquired from the Gene Expression Omnibus (GEO) database. Nonnegative matrix factorization (NMF) was used to identify cell subtypes related to N-glycosylation from a scRNA matrix. Subsequently, a consensus prognostic signature by integrating 101 combinations of 10 machine learning algorithms. The response to immunotherapy in EC was further examined by multiple algorithms. RESULTS Our findings identified 11,020 differentially expressed genes (DEGs), of which 34 N-glycosylation-related DEGs were remarkably associated with overall survival (OS) in EC. Single-cell RNA sequencing analysis revealed 30,233 cells divided into eight clusters, with T cells and epithelial cells showing distinct functional characteristics. NMF clustering further classified malignant cells into four subtypes: N-glycosylation-C0, Glycosphingolipid-C1, O-GalNAc-C2, and Elongation-C3. The O-GalNAc-C2 subtype exhibited the highest metabolic pathway activity and activation of transcription factors SOX4, JUND, and FOS. Additionally, cell-cell interaction networks highlighted the MK signaling pathway as a critical mediator of intercellular communication. An integrated machine learning framework generated a prognostic model comprising eight DEGs (LAMC2, KRT7, IL32, KRT18, SERPINA1, PGR, AKAP12, EDN2), achieving an average C-index of 0.712 in training and validation cohorts. A low-risk score implies more significant immune cell infiltration and better response to immunotherapy. CONCLUSIONS Our study underscores the role of N-glycosylation-related genes in EC prognosis and immunotherapy response prediction, and may provide a basis for the development of targeted therapies and personalized treatment strategies.
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Affiliation(s)
- Min Zhou
- Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Yuefeng Zhang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wei Song
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, No. 238, Jiefang Road, Wuhan, 430060, China.
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Toghraie FS, Bayat M, Hosseini MS, Ramezani A. Tumor-infiltrating myeloid cells; mechanisms, functional significance, and targeting in cancer therapy. Cell Oncol (Dordr) 2025; 48:559-590. [PMID: 39998754 PMCID: PMC12119771 DOI: 10.1007/s13402-025-01051-y] [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] [Accepted: 02/20/2025] [Indexed: 02/27/2025] Open
Abstract
Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.
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Affiliation(s)
- Fatemeh Sadat Toghraie
- Institute of Biotechnology, Faculty of the Environment and Natural Sciences, Brandenburg University of Technology, Cottbus, Germany
| | - Maryam Bayat
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sadat Hosseini
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amin Ramezani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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6
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Rashad AA, Elshafie MF, Mangoura SA, Akool ES. Modulatory effect of metformin and its transporters on immune infiltration in tumor microenvironment: a bioinformatic study with experimental validation. Discov Oncol 2025; 16:973. [PMID: 40450131 DOI: 10.1007/s12672-025-02766-y] [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: 02/22/2025] [Accepted: 05/21/2025] [Indexed: 06/03/2025] Open
Abstract
Metformin is a traditional antidiabetic drug for type 2 diabetes mellitus. However, it showed antitumor activity in many types of tumors, and it also has an influence on tumor metastasis in several types of tumors. It is transported through organic cationic transporters (OCTs), OCT1, OCT2, and OCT3, into the cells or into tumor microenvironment (TME). The complex interaction of metformin and its transporters on immune infiltration in TME of different types of tumors of The Cancer Genomic Atlas (TCGA) is not yet studied. The objective of this study is to identify the most suitable therapeutic target of tumors and immune infiltrates for metformin and its transporters in the TME. TIMER2.0, a bioinformatic tool, and other computational analysis were used to investigate this complex interaction; moreover, the identification of metformin target protein in TME is also investigated. The results revealed that the most suitable therapeutic target for metformin and OCTs among 32 types of TCGA data tumor types is Breast Invasive carcinoma (BRCA), and the most relevant immune infiltrate among 14 types of immune infiltrates that yields better prognosis and better therapeutical effect in TME is Macrophage M1. Furthermore, metformin showed a cytotoxic effect and an inhibitory effect on Urokinase Plasminogen Activator (uPA) gene expression in a concentration dependent fashion in MDA-MB-231 breast cancer cell line. This may suggest that metformin is a promising antitumor drug, stimulant for natural antitumor immune infiltrates, and inhibitor for metastasis in breast cancer.
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Affiliation(s)
- Ahmed A Rashad
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Nasr City, 4434104, Cairo Governorate, Egypt.
| | - Mohamed F Elshafie
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Nasr City, 4434104, Cairo Governorate, Egypt
| | - Safwat A Mangoura
- Department of Clinical Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo, 11829, Egypt
| | - El-Sayed Akool
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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Tang Q, Li L, Ge J, Wang D, Qu H, Wu J, Wang Q, Peng Z, Mo Y, Wang Y, Fan C, Yan Q, Chen P, Huang H, Guo W, Shi L, Zeng Z, Xiong W. m 6A modification-dependent upregulation of WNT2 facilitates M2-like macrophage polarization and perpetuates malignant progression of nasopharyngeal carcinoma. Oncogene 2025:10.1038/s41388-025-03452-7. [PMID: 40419792 DOI: 10.1038/s41388-025-03452-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 04/28/2025] [Accepted: 05/15/2025] [Indexed: 05/28/2025]
Abstract
The development and progression of nasopharyngeal carcinoma (NPC) involves intricate interactions between tumor cells and other surrounding cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play pivotal roles in the progression of NPC, but their interactions remain largely unexplored. In this study, we revealed that NPC promoted M2-like polarization of TAMs through enhanced synthesis and secretion of WNT2. These M2-type macrophages, in turn, significantly boosted the proliferation and metastasis of NPC. This vicious cycle perpetuated the malignant progression of NPC. Mechanistically, elevated m6A modification of WNT2 in NPC stabilized its mRNA and facilitated its protein expression, which is coordinately regulated by the m6A "eraser" ALKBH5 and the "reader" YTHDF1. NPC promoted M2-like polarization of macrophages by activating the FZD2/β-catenin signaling axis through paracrine WNT2. Furthermore, elevated WNT2 can also trigger the WNT/β-catenin signaling pathway in NPC cells through autocrine signaling, synergically contributing to NPC development. The research reveals that WNT2 is upregulated in an m6A modification-dependent manner and promotes M2-like macrophages polarization of TAMs and malignant progression of NPC. This discovery provides novel potential molecular markers and therapeutic targets for the diagnosis and treatment of NPC.
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Affiliation(s)
- Qiling Tang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
| | - Lvyuan Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
| | - Junshang Ge
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Dan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Hongke Qu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Jie Wu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Departments of Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
- Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, China
| | - Qian Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Zhouying Peng
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yongzhen Mo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yumin Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Departments of Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunmei Fan
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Qijia Yan
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Pan Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - He Huang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
- FuRong Laboratory, Changsha, Hunan, China
| | - Wenjia Guo
- Departments of Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
- Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, China
| | - Lei Shi
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China.
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China.
- FuRong Laboratory, Changsha, Hunan, China.
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China.
- FuRong Laboratory, Changsha, Hunan, China.
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Zheng S, Wang C, Fu J, Shao J. Investigating Overlapping Immune-related Genetic Markers in Cholangiocarcinoma and Inflammatory Bowel Disease for Predictive Prognosis. J Immunother 2025:00002371-990000000-00142. [PMID: 40384613 DOI: 10.1097/cji.0000000000000562] [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: 02/07/2025] [Accepted: 04/09/2025] [Indexed: 05/20/2025]
Abstract
This study aims to explore the common immune-related gene characteristics of cholangiocarcinoma (CHOL) and inflammatory bowel disease (IBD) to predict disease prognosis. By analyzing the gene expression data from the TCGA, GEO, and NGDC databases, differentially expressed immune-related genes (DE-IRGs) were screened, and a prognostic model was constructed. The results showed that CCR7, OSM, S100P, ACVR1C, OSMR, SPP1, and PIK3R3 were key immune-related genes, and their expressions were closely related to the occurrence and development of CHOL and IBD. Patients in the low immune risk score (IRS) group had more abundant antitumor immune cell infiltration, while those in the high IRS group had more macrophage infiltration. In addition, the model based on these genes had good predictive ability for the diagnosis and prognosis of CHOL and IBD, with an area under the ROC curve (AUC) value exceeding 0.7. This study also predicted potential small molecule drugs that might be effective for the treatment of CHOL, such as Umbralisib and Tamoxifen. In conclusion, this study provides new biomarkers and potential targets for diagnosis, prognosis assessment, and treatment of CHOL and IBD.
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Affiliation(s)
| | | | | | - Jinfan Shao
- Colorectal Surgery, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital
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Newnes HV, Armitage JD, Buzzai AC, de Jong E, Audsley KM, Barnes SA, Srinivasan S, Serralha M, Fear VS, Guo BB, Jones ME, Forrest ARR, Foley B, Darcy PK, Beavis PA, Bosco A, Waithman J. Interleukin-4 modulates type I interferon to augment antitumor immunity. SCIENCE ADVANCES 2025; 11:eadt3618. [PMID: 40367186 PMCID: PMC12077506 DOI: 10.1126/sciadv.adt3618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 04/09/2025] [Indexed: 05/16/2025]
Abstract
Despite advances in immunotherapy, metastatic melanoma remains a considerable therapeutic challenge due to the complexity of the tumor microenvironment. Intratumoral type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumor growth in some contexts. We investigated this further by engineering murine B16 melanoma cells to overexpress various IFN-I subtypes, where a spectrum of outcomes was observed. Characterization of these tumors by RNA sequencing revealed a tumor immune phenotype, where potent IFN-I signaling concomitant with diminished type 2 inflammation failed to confer durable tumor control. T cell-mediated rejection of these tumors was restored by introducing interleukin-4 (IL-4) into the tumor microenvironment, either through ectopic expression or in a preclinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting antitumor immunity, which could be harnessed to target and stratify solid tumors that are nonresponsive to frontline therapies.
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Affiliation(s)
- Hannah V. Newnes
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Jesse D. Armitage
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Anthony C. Buzzai
- Department of Dermatology, Otto-von-Guericke University, Magdeburg, Germany
| | - Emma de Jong
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Katherine M. Audsley
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Samantha A. Barnes
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Shamini Srinivasan
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
| | - Michael Serralha
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Vanessa S. Fear
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Belinda B. Guo
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
| | - Matt E. Jones
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Australia
| | - Alistair R. R. Forrest
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Australia
| | - Bree Foley
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
| | - Phil K. Darcy
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Department of Pathology, The University of Melbourne, Melbourne, Australia
- Department of Immunology, Monash University, Melbourne, Australia
| | - Paul A. Beavis
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Anthony Bosco
- Department of Immunobiology, The University of Arizona, Tucson, AZ, USA
| | - Jason Waithman
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
- The Kids Research Institute Australia, The University of Western Australia, Perth, Australia
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10
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Wang Q, Gong Y, Li J, Luo D, Zeng X, Ling Y, Zhou Y, Chen Z. Topology-dependent T2 relaxivity in Fe 3O cluster-based MOFs for enhanced tumor monitoring via MRI. J Mater Chem B 2025; 13:5521-5529. [PMID: 40163109 DOI: 10.1039/d4tb02858a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Metal-organic frameworks (MOFs) are crystalline porous materials with tunable structures, where metal ions or clusters serve as magnetic centers and organic ligands offer spatial separation. These characteristics, combined with their diverse topologies, make MOFs promising candidates for contrast agents (CAs) in magnetic resonance imaging (MRI). Herein we synthesized four MOFs based on the same triangular Fe3O clusters with different topologies: MIL-101(Fe) (moo net), MIL-100(Fe) (mtn net), MIL-59(Fe) (pcu net), and MIL-88B(Fe) (acs net). To clarify the relationship between topologies and T2 relaxivities, the MOFs were tailored into uniform, nanoscale spherical morphologies. Notably, the value of T2 relaxivity for MIL-88B(Fe) with acs topology is nearly three times that for MIL-101(Fe) with moo topology at 7.0 T. By comparing the magnetic properties of Fe3O molecular clusters and Ga-doped MIL-88B(Fe), our analysis demonstrated the significant advantage of MOFs with fixed arrays, adjustable components and diverse topologies in enhancing magnetic relaxation. Cellular MRI experiments further revealed that MIL-88B(Fe) could differentiate between M1 and M2 macrophages, highlighting its potential for monitoring tumor progression. These findings offer valuable insights into how MOF topology can be strategically utilized to enhance T2 relaxivities for MRI applications.
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Affiliation(s)
- Qiao Wang
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Yimin Gong
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Jianing Li
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Dan Luo
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Xin Zeng
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Yun Ling
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Yaming Zhou
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Zhenxia Chen
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
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11
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Kong M, Zhai Y, Liu H, Zhang S, Chen S, Li W, Ma X, Ji Y. Insights into the mechanisms of angiogenesis in hepatoblastoma. Front Cell Dev Biol 2025; 13:1535339. [PMID: 40438141 PMCID: PMC12116456 DOI: 10.3389/fcell.2025.1535339] [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: 11/27/2024] [Accepted: 05/02/2025] [Indexed: 06/01/2025] Open
Abstract
Hepatoblastoma (HB), the most common pediatric liver malignancy, is characterized by aggressive growth and metastasis driven by complex angiogenic mechanisms. This review elucidates the pivotal role of angiogenesis in HB progression, emphasizing metabolic reprogramming, tumor microenvironment (TME) dynamics, and oncogenic signalling pathways. The Warburg effect in HB cells fosters a hypoxic microenvironment, stabilizing hypoxia-inducible factor-1α (HIF-1α) and upregulating vascular endothelial growth factor (VEGF), which synergistically enhances angiogenesis. Key pathways such as the Wnt/β-catenin, VEGF, PI3K/AKT, and JAK2/STAT3 pathways are central to endothelial cell proliferation, migration, and vascular maturation, whereas interactions with tumor-associated macrophages (TAMs) and pericytes further remodel the TME to support neovascularization. Long noncoding RNAs and glycolytic enzymes have emerged as critical regulators of angiogenesis, linking metabolic activity with vascular expansion. Anti-angiogenic therapies, including VEGF inhibitors and metabolic pathway-targeting agents, show preclinical promise but face challenges such as resistance and off-target effects. Future directions advocate for dual-target strategies, spatial multiomics technologies to map metabolic-angiogenic crosstalk, and personalized approaches leveraging biomarkers for risk stratification. This synthesis underscores the need for interdisciplinary collaboration to translate mechanistic insights into durable therapies, ultimately improving outcomes for HB patients.
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Affiliation(s)
- Meng Kong
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Yunpeng Zhai
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Hongzhen Liu
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Shisong Zhang
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Shuai Chen
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Wenfei Li
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiang Ma
- Department of Respiratory Disease, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Jinan Key Laboratory of Pediatric Respiratory Diseases, Jinan Children’s Hospital, Jinan, China
| | - Yi Ji
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
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Jin X, Zhang N, Yan T, Wei J, Hao L, Sun C, Zhao H, Jiang S. Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential. Front Immunol 2025; 16:1573039. [PMID: 40433363 PMCID: PMC12106438 DOI: 10.3389/fimmu.2025.1573039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.
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Affiliation(s)
- Xiaohan Jin
- Center for Post-Doctoral Studies, Shandong University of Traditional Chinese Medicine, Jinan, China
- Clinical Medical Laboratory Center, Jining No.1 People’s Hospital, Jining, China
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tinghao Yan
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingyang Wei
- Second College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lingli Hao
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Changgang Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haibo Zhao
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining No.1 People’s Hospital, Jining, China
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
- Second College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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Sutera S, Furchì OA, Pentenero M. Macrophages and the immune microenvironment in OPMDs: a systematic review of the literature. FRONTIERS IN ORAL HEALTH 2025; 6:1605978. [PMID: 40432828 PMCID: PMC12106459 DOI: 10.3389/froh.2025.1605978] [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: 04/04/2025] [Accepted: 04/17/2025] [Indexed: 05/29/2025] Open
Abstract
Background In the presence of cancers, Tumor Associated Macrophages have a well-established role, but the literature provides limited evidence regarding their involvement in the onset and malignant transformation of Oral Potentially Malignant Disorders (OPMDs). Objectives The present systematic review aimed to collect evidence on the presence and characterization of macrophages in the microenvironment of OPMDs. Data sources PubMed, Scopus, EMBASE, Web of Science. Study eligibility criteria Ex vivo or in silico human studies reporting original quantitative data on macrophage infiltration in OPMDs or Oral Epithelial Dysplasia (OED), published from 1990 onward. Results Thirty-seven studies were included for qualitative analysis. Investigated OPMDs included: oral leukoplakia, oral lichen planus, oral lichenoid lesions, proliferative leukoplakia, oral submucous fibrosis, actinic cheilitis, chronic graft vs. host disease. Discussion Even though the heterogeneity of data from the included studies prevents a meta-analysis, the reported results are quite consistent in supporting an increasing macrophage infiltration from normal mucosa to OPMDs, OED, and Oral Squamous Cell Carcinoma (OSCC). An M1 pro-inflammatory polarization is prevalent in OPMDs, with a shift toward an M2 pro-tumorigenic polarization in moderate-severe OED and OSCC. Several novel markers including STAT1, IDO, PD-L1, APOE, ITGB2 appear to be able to identify macrophage clusters involved in pro-inflammatory or pro-tumorigenic pathways. Conclusions Evidence from the present review supports an active role of macrophages in regulating immune suppression, oncogenesis, and tumor progression in OPMDs and during the transition to OSCC. Future research should focus not merely on cell quantification and general M1/M2 polarization but rather on the expression of specific markers potentially linked to immunomodulatory pathways involved in oncogenesis.
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Liang H, Zhang S. Thrombospondin-1 induces CD8 + T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer. J Ovarian Res 2025; 18:99. [PMID: 40349060 PMCID: PMC12065243 DOI: 10.1186/s13048-025-01668-5] [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: 12/11/2024] [Accepted: 04/10/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Ovarian cancer (OC) progression is heavily influenced by the tumor microenvironment (TME), where immune suppression plays a critical role. This study explores the role of thrombospondin-1 (THBS1) in regulating tumor-associated macrophages (TAMs), T cell exhaustion, and immune checkpoint expression, as well as its transcriptional regulation by SNF2H. METHODS We analyzed THBS1 expression and its clinical significance using publicly available datasets (TCGA-OV, GSE14407) and tissue microarrays containing OC and adjacent normal tissues. In vitro functional studies were conducted using OC cell lines (SKOV3, A2780) and co-cultures with macrophages. Chromatin immunoprecipitation (ChIP) assays and RNA interference were employed to investigate SNF2H-mediated transcriptional regulation of THBS1. In vivo, the role of THBS1 in immune suppression was validated using mouse tumor models. RESULTS THBS1 was significantly overexpressed in OC tissues and associated with poor prognosis. High levels of THBS1 correlated with increased TAM infiltration, M2 macrophage polarization, and upregulation of immune checkpoints PD-L1 and GAL-3, which contribute to T cell exhaustion. Functional assays demonstrated that THBS1 promotes macrophage recruitment and induces M2 polarization through TGF-β1 and IL-4 signaling. Additionally, ChIP assays identified SNF2H as a transcriptional regulator of THBS1, contributing to its overexpression. In vitro targeting of THBS1 reduced TAM-mediated immune suppression and restored T cell cytotoxicity. CONCLUSION This study positions THBS1 as a key regulator of the OC TME, linking TAM recruitment and polarization to CD8+ T cell exhaustion via immune checkpoint modulation. By identifying SNF2H as a transcriptional regulator of THBS1, we offer new insights into its epigenetic dysregulation and suggest potential therapeutic strategies to reprogram the TME and improve the effectiveness of immunotherapy.
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Affiliation(s)
- Haiyan Liang
- Department of Reproductive Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515031, Guangdong, China
| | - Suwei Zhang
- Department of Clinical Laboratory, Shantou Central Hospital, No.114 of Waima Road, Shantou, 515041, Guangdong, China.
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15
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Zeng J, Wang D, Tong Z, Li Z, Wang G, Du Y, Li J, Miao J, Chen S. Development of a prognostic model for osteosarcoma based on macrophage polarization-related genes using machine learning: implications for personalized therapy. Clin Exp Med 2025; 25:146. [PMID: 40343502 PMCID: PMC12064610 DOI: 10.1007/s10238-024-01530-w] [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: 08/31/2024] [Accepted: 11/25/2024] [Indexed: 05/11/2025]
Abstract
While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. BNIP3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, BNIP3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.
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Affiliation(s)
- Jin Zeng
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - Dong Wang
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - ZhaoChen Tong
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - ZiXin Li
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - GuoWei Wang
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - YuMeng Du
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - Jinsong Li
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - Jinglei Miao
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China
| | - Shijie Chen
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, 410013, Hunan, China.
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
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Zhang Y, Xu Y, Zhong W, Zhao J, Liu X, Gao X, Chen M, Wang M. Vitamin D and Immune Checkpoint Inhibitors in Lung Cancer: A Synergistic Approach to Enhancing Treatment Efficacy. Int J Mol Sci 2025; 26:4511. [PMID: 40429656 PMCID: PMC12111780 DOI: 10.3390/ijms26104511] [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: 03/15/2025] [Revised: 04/27/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Lung cancer, a malignant neoplasm that is globally prevalent and characterized by high incidence and mortality rates, has seen the rise of immune checkpoint inhibitors (ICIs) as a crucial systemic treatment. However, a subset of patients exhibits suboptimal responses to ICIs. Recently, studies revealed the role of vitamin D in inflammation modulation, cell differentiation, and cancer prevention. Vitamin D precisely modulates immune responses and inflammatory states within the tumor microenvironment (TME) by targeting both innate and adaptive immunity. These effects may reduce immune tolerance to ICIs and synergistically enhance their therapeutic efficacy. Here, we review vitamin D metabolism in lung cancer patients, as well as its anti-tumor mechanisms, immune regulation, and the significant promise of vitamin D in lung cancer immunotherapy and adjuvant therapeutic strategies. Further research is imperative to surmount these challenges and fully realize vitamin D's potential in improving lung cancer immunotherapy outcomes.
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Affiliation(s)
| | | | | | | | | | | | - Minjiang Chen
- Department of Respiratory & Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (Y.Z.); (Y.X.); (W.Z.); (J.Z.); (X.L.); (X.G.); (M.W.)
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17
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Liu Z, Deng X, Wang Z, Guo Y, Hameed MMA, El-Newehy M, Zhang J, Shi X, Shen M. A biomimetic therapeutic nanovaccine based on dendrimer-drug conjugates coated with metal-phenolic networks for combination therapy of nasopharyngeal carcinoma: an in vitro investigation. J Mater Chem B 2025; 13:5440-5452. [PMID: 40241472 DOI: 10.1039/d5tb00226e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Developing a minimally invasive and potent therapy for nasopharyngeal carcinoma is still challenging. In this study, we report a photothermal nanovaccine based on phenylboronic acid (PBA)-modified poly(amidoamine) dendrimers of generation 5 (G5) attached with indocyanine green (ICG) as a photothermal agent, toyocamycin (Toy) as an endoplasmic reticulum stress (ERS) drug, and Mn2+-coordinated metal-phenolic networks. The developed nanocomplexes are camouflaged with homologous apoptotic cancer cell membranes, leveraging membrane proteins as an antigenic reservoir and incorporating the immune adjuvant cytosine-guanine (CpG) oligonucleotide to obtain the final nanovaccine formulation. The prepared nanovaccine with a size of 72.4 nm displays satisfactory colloidal stability and photothermal conversion efficiency (36.7%), and is capable of targeting cancer cells and inducing apoptosis under laser irradiation through combined ICG-mediated photothermal therapy, Toy-enabled chemotherapy and Mn2+-mediated chemodynamic therapy. Meanwhile, the combined therapeutic effects can elicit immune responses to mature dendritic cells through the immunogenic cell death of cancer cells and the inserted CpG adjuvant/apoptotic cancer cell membranes, and polarize tumor-associated macrophage cells to the antitumor M1 phenotype. The antitumor efficacy of the nanomedicine platform was proven by the test of the penetration and therapeutic inhibition of 3-dimensional tumor spheroids in vitro. The developed functional nanomedicine integrated with different therapeutic modes may be developed as a biomimetic therapeutic nanovaccine for nasopharyngeal carcinoma treatment.
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Affiliation(s)
- Zhiyun Liu
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
| | - Xiaochun Deng
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
| | - Zhiqiang Wang
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
| | - Yunqi Guo
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
| | - Meera Moydeen Abdul Hameed
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Mohamed El-Newehy
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Jianjun Zhang
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
| | - Xiangyang Shi
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
| | - Mingwu Shen
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
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Liu N, Wu T, Han G, Chen M. Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application. Cell Death Discov 2025; 11:221. [PMID: 40328736 PMCID: PMC12056189 DOI: 10.1038/s41420-025-02484-y] [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: 02/15/2025] [Revised: 04/01/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.
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Affiliation(s)
- Na Liu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Tianqing Wu
- XJTLU Wisdom Lake Academy of Pharmacy, Suzhou, Jiangsu Province, China
| | - Guohu Han
- Department of Oncology, Jingjiang People's Hospital Affiliated with Yangzhou University, Jingjiang, China
| | - Minbin Chen
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
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Zhao Y, Pei L, Liu B, Mao Z, Niu Y, Li S, Yang M, Liu W, Hai H, Luo Y, Liu T. Macrophage Membrane-Coated Nanomedicine Enhances Cancer Immunotherapy by Activating Macrophages and T Cells. Mol Pharm 2025; 22:2402-2412. [PMID: 40266070 DOI: 10.1021/acs.molpharmaceut.4c00950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
Cancer immunotherapy has transformed malignancy treatment, but the tumor microenvironment (TME) presents significant obstacles. PD-1 blockade therapy, while widely used, faces issues such as resistance, adverse events, and limited predictive biomarkers. Therefore, novel therapeutic strategies are needed to enhance their efficacy and safety. Tumor-associated macrophages (TAMs), often exhibiting an anti-inflammatory M2 phenotype, contribute to poor prognoses and treatment resistance. Targeting TAMs to repolarize them to a pro-inflammatory M1 state can alleviate immunosuppression and enhance T cell-mediated antitumor responses. TMP195, a class IIa histone deacetylase inhibitor, has shown potential in reprogramming TAMs and synergizing with anti-PD-1 antibodies, although clinical application challenges exist. This study aimed to enhance the PD-1 blockade immunotherapy effectiveness by activating tumor-killing macrophages and T cells using biomimetic nanomedicines. A novel macrophage cell membrane-coated PLGA nanoparticle loaded with small molecule inhibitor, TMP195 (M1@PLGA-PEG-TMP195), was designed, prepared, and characterized. This macrophage membrane-coated PLGA nanoparticle delivery system had good drug loading and cancer cell targeting ability. This approach repolarized TAMs to M1 phenotypes and, combined with PD-1 inhibitors, achieved synergistic cancer treatment effects, improving therapeutic efficacy and inhibiting breast cancer growth and metastasis.
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Affiliation(s)
- Yongmei Zhao
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Lulu Pei
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Baolin Liu
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Zehao Mao
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Yingyi Niu
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Siqi Li
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Meiqing Yang
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Wenqian Liu
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Hongde Hai
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Yunyao Luo
- School of Pharmacy, Nantong University, Nantong 226019, China
| | - Tianqing Liu
- NICM Health Research Institute, Western Sydney University, Westmead, Sydney 2145, Australia
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20
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Yang Y, Wang X, Wu L, Zhao S, Chen R, Yu G. Identification and validation of susceptibility modules and hub genes of adrenocortical carcinoma through WGCNA and machine learning. Discov Oncol 2025; 16:663. [PMID: 40317315 PMCID: PMC12049343 DOI: 10.1007/s12672-025-02396-4] [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: 09/24/2024] [Accepted: 04/15/2025] [Indexed: 05/07/2025] Open
Abstract
PURPOSE Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy characterized by rapid progression, significantly impacting patients' quality of life. Analyzing gene co-expression modules offers valuable insights into the molecular mechanisms driving ACC progression. In this study, we applied Weighted Gene Co-Expression Network Analysis (WGCNA) to identify gene co-expression modules associated with ACC progression. METHODS Before conducting WGCNA, differential gene expression and immune infiltration analyses were performed on the GSE90713 dataset (available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi ). Dynamic tree cutting was utilized to identify co-expression modules, which were subsequently analyzed to determine their correlations and associations with traits. A total of 21 co-expression modules were identified, with the yellow module demonstrating a strong correlation with the progression of ACC. Enrichment analysis was carried out on differentially expressed genes, the yellow module, cross-module interactions, and the final hub genes to identify the associated Biological Processes (BPs) and pathways relevant to ACC. Additionally, the CIBERSORT algorithm was employed to predict immune cell infiltration in ACC. RESULTS The enrichment analysis revealed that pathways associated with cell division, protein synthesis, and metabolism play significant roles in the progression of ACC. Additionally, CDK1, AURKA, CCNB2, BIRC5, CCNB1, TYMS, and TOP2A were identified as key regulatory hub genes. Survival analysis further demonstrated that elevated expression levels of these genes in ACC tissues are significantly correlated with lower overall survival rates in patients, underscoring their critical involvement in ACC development and progression. CONCLUSION This study sheds light on the mechanisms underlying ACC progression and highlights potential therapeutic targets. By identifying specific immune cell subtypes associated with ACC, the findings may aid in developing immune modulation therapies aimed at preventing or treating ACC.
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Affiliation(s)
- Yaoming Yang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Xinbao Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Liuqing Wu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Shihua Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Ran Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Guoyong Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China.
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21
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Xu Y, Zhang H, Nie D. Histone modifications and metabolic reprogramming in tumor-associated macrophages: a potential target of tumor immunotherapy. Front Immunol 2025; 16:1521550. [PMID: 40375990 PMCID: PMC12078272 DOI: 10.3389/fimmu.2025.1521550] [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: 11/04/2024] [Accepted: 04/09/2025] [Indexed: 05/18/2025] Open
Abstract
Histone modifications, including methylation, acetylation, lactylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, and crotonylation, critically regulate tumor-associated macrophages (TAMs) polarization by modulating gene expression and functional states. Reprogramming TAMs from M2 to M1 phenotypes through epigenetic targeting has emerged as a promising strategy to enhance anti-tumor immunity and improve the efficacy of cancer immunotherapy. This review explores the role of histone modifications in TAM biology, their interplay with metabolic reprogramming, and the opportunities and challenges in developing epigenetic-based therapies to advance cancer immunotherapy.
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Affiliation(s)
- Yiting Xu
- The Second Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Han Zhang
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dengyun Nie
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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22
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Summer M, Riaz S, Ali S, Noor Q, Ashraf R, Khan RRM. Understanding the Dual Role of Macrophages in Tumor Growth and Therapy: A Mechanistic Review. Chem Biodivers 2025; 22:e202402976. [PMID: 39869825 DOI: 10.1002/cbdv.202402976] [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: 11/12/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/29/2025]
Abstract
Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.
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Affiliation(s)
- Muhammad Summer
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Saima Riaz
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Shaukat Ali
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Qudsia Noor
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Rimsha Ashraf
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Rana Rashad Mahmood Khan
- Faculty of Chemistry and Life Sciences, Department of Chemistry, Government College University Lahore, Lahore, Pakistan
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23
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Zhang H, Yu Y, Qian C. Oligonucleotide-Based Modulation of Macrophage Polarization: Emerging Strategies in Immunotherapy. Immun Inflamm Dis 2025; 13:e70200. [PMID: 40325939 PMCID: PMC12053320 DOI: 10.1002/iid3.70200] [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: 06/26/2024] [Revised: 03/10/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Recent advances in immunotherapy have spotlighted macrophages as central mediators of disease treatment. Their polarization into pro‑inflammatory (M1) or anti‑inflammatory (M2) states critically influences outcomes in cancer, autoimmunity, and chronic inflammation. Oligonucleotides have emerged as highly specific, scalable, and cost‑effective agents for reprogramming macrophage phenotypes. OBJECTIVE To review oligonucleotide strategies-including ASOs, siRNAs, miRNA mimics/inhibitors, and aptamers-for directing macrophage polarization and their therapeutic implications. REVIEW SCOPE We examine key signaling pathways governing M1/M2 phenotypes, describe four classes of oligonucleotides and their mechanisms, and highlight representative preclinical and clinical applications. KEY INSIGHTS Agents such as AZD9150, MRX34, and AS1411 demonstrate macrophage reprogramming in cancer, inflammation, and infection models. Advances in ligand‑conjugated nanoparticles and chemical modifications improve delivery and stability, yet immunogenicity, off‑target effects, and formulation challenges remain significant barriers. FUTURE PERSPECTIVES Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation.
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Affiliation(s)
- Hanfu Zhang
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
- School of Molecular SciencesUniversity of Western AustraliaCrawleyWAAustralia
| | - Yizhi Yu
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
| | - Cheng Qian
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
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24
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Zhang L, Wang K, Li F, Zhang L, Wu L, Tie R, Litifu K, Fu Y, Liu S, Ni J, Chang P, Xu J, Zhao H, Liu L. Ribosomal protein S3A (RPS3A), as a transcription regulator of colony-stimulating factor 1 (CSF1), promotes glioma progression through regulating the recruitment and autophagy-mediated M2 polarization of tumor-associated macrophages. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:5437-5452. [PMID: 39560749 DOI: 10.1007/s00210-024-03601-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/01/2024] [Indexed: 11/20/2024]
Abstract
Dysregulated expression of ribosomal protein S3A (RPS3A) is associated with the tissue infiltration of immune-related cells in a variety of cancers. However, the role of RPS3A in immune cell infiltration in glioma remains unclear. This study aimed to explore the role of RPS3A in the glioma immune microenvironment. RPS3A expression was detected in tumor tissues from patients with glioma. U251 cells were transfected with RPS3A shRNA (sh-RPS3A) and overexpression vector (pcDNA-RPS3A) and then co-cultured with PMA-induced THP-1 cells. Cell viability, invasion, and apoptosis were detected by Edu staining, Transwell, and flow cytometry, respectively. The expression of tumor-associated macrophage (TAM) M1 and M2 markers was detected with RT-qPCR. Next, the interaction between RPS3A and E4 transcription factor 1 (E4F1) was verified by Co-IP analysis, and the binding of E4F1 to colony-stimulating factor 1 (CSF1) promoter was verified by ChIP analysis. Overexpression vectors of CSF1 and E4F1 were used to treat sh-RPS3A-transfected U251 cells for reversal experiments. Finally, U251 cells transfected with sh-RPS3A adenovirus vectors were subcutaneously injected into nude mice to construct a xenograft tumor model, and the growth and metastasis of glioma in vivo were monitored. RPS3A was significantly upregulated in glioma tissues. Overexpression of RPS3A promoted glioma cell proliferation and invasion and inhibited apoptosis. Moreover, overexpression of RPS3A promoted TAM proliferation, invasion, and M2 polarization. Silencing RPS3A had the opposite effect. Silencing RPS3A inhibited autophagy in U251 cells, whereas rapamycin, an activator of autophagy, reversed the inhibitory effect of RPS3A silencing on TAM M2 polarization. Meanwhile, RPS3A promoted its expression by interacting with E4F1, and E4F1 promoted CSF1 transcriptional activation. Overexpression of CSF1 promoted the proliferation and invasion of U251 cells and reversed the inhibitory effect of RPS3A silencing on TAM proliferation and invasion, but had no effect on TAM M2 polarization. The results of in vivo experiments showed that knockdown of RPS3A significantly inhibited glioma tumor growth and metastasis in vivo. This study revealed that RPS3A recruited TAMs by upregulating E4F1-mediated transcription activation of CSF1, and promoted the M2 polarization of TAMs through autophagy, promoting glioma cell malignant growth and tumor progression.
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Affiliation(s)
- Liang Zhang
- Northwest University, Guodu Education and Technology Industrial Zone, No. 1 Xuefu Street, Chang'an District, Xi'an, 710127, China
- Xi'an Daxing Hospital, No. 353 Laodong North Road, Lianhu District, Xi'an, 710016, China
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Kun Wang
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Fei Li
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Lingxue Zhang
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Lin Wu
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Ru Tie
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Kamulan Litifu
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Yujie Fu
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Simeng Liu
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Jiaxin Ni
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Pan Chang
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China
| | - Jun Xu
- Xi'an Daxing Hospital, No. 353 Laodong North Road, Lianhu District, Xi'an, 710016, China
| | - Haikang Zhao
- Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an, 710038, China.
| | - Lingtong Liu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No.32 West Second Section First Ring Road, Chengdu, 610072, China.
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25
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Tuo Z, Gao M, Jiang C, Zhang D, Chen X, Jiang Z, Wang J. Construction of M2 macrophage-related gene signature for predicting prognosis and revealing different immunotherapy response in bladder cancer patients. Clin Transl Oncol 2025; 27:2191-2206. [PMID: 39347941 DOI: 10.1007/s12094-024-03698-9] [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: 06/12/2024] [Accepted: 08/22/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Bladder cancer development is closely associated with the dynamic interaction and communication between M2 macrophages and tumor cells. However, specific biomarkers for targeting M2 macrophages in immunotherapy remain limited and require further investigation. METHODS In this study, we identified key co-expressed genes in M2 macrophages and developed gene signatures to predict prognosis and immunotherapy response in patients. Public database provided the bioinformatics data used in the analysis. We created and verified an M2 macrophage-related gene signature in these datasets using Lasso-Cox analysis. RESULTS The predictive value and immunological functions of our risk model were examined in bladder cancer patients, and 158 genes were found to be significantly positively correlated with M2 macrophages. Moreover, we identified two molecular subgroups of bladder cancer with markedly different immunological profiles and clinical prognoses. The five key risk genes identified in this model were validated, including CALU, ECM1, LRP1, CYTL1, and CCDC102B, demonstrating the model can accurately predict prognosis and identify unique responses to immunotherapy in patients with bladder cancer. CONCLUSIONS In summary, we constructed and validated a five-gene signature related to M2 macrophages, which shows strong potential for forecasting bladder cancer prognosis and immunotherapy response.
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Affiliation(s)
- Zhouting Tuo
- Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Mingzhu Gao
- Department of Oncology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Chao Jiang
- Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Duobing Zhang
- Department of Urology, Suzhou Hospital of Anhui Medical University, Suzhou, 234000, China
- Department of Urology, Suzhou Municipal Hospital of Anhui Province, Suzhou, 234000, China
| | - Xin Chen
- Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Zhiwei Jiang
- Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
| | - Jinyou Wang
- Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
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26
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Zhang Y, He H, Fu X, Liu G, Wang H, Zhong W, Xu X, Chen B, Mei L. Glioblastoma-associated macrophages in glioblastoma: from their function and mechanism to therapeutic advances. Cancer Gene Ther 2025:10.1038/s41417-025-00905-9. [PMID: 40307579 DOI: 10.1038/s41417-025-00905-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 04/01/2025] [Accepted: 04/07/2025] [Indexed: 05/02/2025]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults and has high mortality rates worldwide. GBM progression, treatment, and prognosis are influenced by the tumor microenvironment (TME), which includes immune, stromal, and tumor cells. Among them, glioblastoma-associated macrophages (GAMs) act as key regulators of GBM pathobiology. GAMs exhibit remarkable plasticity, as they can exhibit both protumor and antitumor effects. However, their function is determined by polarization and the TME. In this review, we provide a comprehensive overview of the current understanding of the biology of GAMs in GBM, including their origins, phenotypic diversity, and functional roles. We discuss the intricate crosstalk between GAMs and tumor cells, as well as other immune and stromal components, and highlight the mechanisms underlying GAM-mediated tumor progression, invasion, angiogenesis, and immune system evasion. Furthermore, we explore the therapeutic implications of targeting GAMs in GBM and discuss emerging strategies aimed at reprogramming GAMs toward an antitumorigenic phenotype or selectively depleting protumorigenic subsets. The final aim is to develop innovative therapeutic approaches that disrupt GBMs. By leveraging our increased understanding of GAM biology, we lay the foundation for transformative advances in GBM treatment to improve patient prognosis.
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Affiliation(s)
- Yuqin Zhang
- Department of General Practice, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hanxing He
- Department of Orthopedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Xin Fu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Ganzhi Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Huiying Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wen Zhong
- Department of General Practice, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xia Xu
- Department of General Practice, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Bo Chen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
| | - Lin Mei
- Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, Tianjin, China.
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27
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de la Rosa I, Sisó P, Ríos C, Gracia J, Cuevas D, Maiques O, Eritja N, Soria X, Angel-Baldó J, Gatius S, Sanchez-Moral L, Sarrias MR, Matias-Guiu X, Martí RM, Macià A. High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma. Int J Mol Sci 2025; 26:4097. [PMID: 40362334 PMCID: PMC12071846 DOI: 10.3390/ijms26094097] [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: 03/19/2025] [Revised: 04/16/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Acral lentiginous melanoma (ALM) is a rare melanoma subtype primarily located in acral regions. However, ALMs exhibit a distinctive genetic profile characterized by a high number of copy number variations (CNVs) and limited point mutations. Late diagnosis and restricted therapeutic efficacy contribute to its poor prognosis. The secretome within the tumor microenvironment (TME) influences immune modulation and plays a vital role in melanoma progression. We aim to analyze the role of ALM secretome and CNVs profile with prognosis in primary ALM patients. Here, we demonstrated that high CNV burden (CNVsHigh) was associated with worse clinicopathological characteristics and poor prognosis. Furthermore, our study also revealed that conditioned media (CM) of CNVsHigh genetic profile ALM cell line was associated with pro-tumoral, pro-angiogenic, and immunosuppressive secretome profiles. In addition, CM of CNVsHigh cell lines in vitro promotes macrophage polarization to immunosuppressive phenotype. Moreover, we observed an increased presence of immunosuppressive tumor-associated macrophages (TAMs) at the invasive front (IF) of CNVsHigh ALM biopsies. This research reveals the adverse prognostic impact of CNVsHigh in ALM patients, establishing a novel link with a pro-tumor secretome, offering potential biomarkers for prognosis and personalized treatment to enhanced disease monitoring in ALM patients.
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Affiliation(s)
- Inés de la Rosa
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Pol Sisó
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Christopher Ríos
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Judith Gracia
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Dolors Cuevas
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Oscar Maiques
- Cytoskeleton and Cancer Metastasis Group, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SM2 5NG, UK;
- Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK
| | - Núria Eritja
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Xavier Soria
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Joan Angel-Baldó
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Sonia Gatius
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Lidia Sanchez-Moral
- Innate Immunity Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; (L.S.-M.); (M.-R.S.)
| | - Maria-Rosa Sarrias
- Innate Immunity Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; (L.S.-M.); (M.-R.S.)
- Center for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), 28029 Madrid, Spain
| | - Xavier Matias-Guiu
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Rosa M. Martí
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Anna Macià
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
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Kobayashi H, Shigetomi H, Imanaka S. Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions. Cancers (Basel) 2025; 17:1447. [PMID: 40361374 PMCID: PMC12071115 DOI: 10.3390/cancers17091447] [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: 02/25/2025] [Revised: 04/20/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
OBJECTIVES Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor that suppresses tumors by preventing extracellular matrix degradation and invasion. In many malignancies, the TFPI2 promoter hypermethylation silences its transcription, increasing tumor aggressiveness. However, TFPI2 paradoxically facilitates tumor progression in certain malignancies. Elevated circulating TFPI2 levels correlate with increased cancer aggressiveness and poor prognosis in ovarian, endometrial, and renal cell carcinoma, though the mechanisms underlying its tumor-promoting effects remain unclear. This review consolidates recent findings on TFPI2 regulation, its downstream targets in cellular homeostasis, and its prognostic significance. Additionally, we reassess TFPI2's role in tumorigenesis, particularly in clear cell carcinoma, as well as in chronic inflammation. METHODS A comprehensive literature search was performed in PubMed and Google Scholar without time restriction. RESULTS TFPI2 expression is tightly regulated by transcription factors, signaling molecules, growth factors, cytokines, and epigenetic modification. TFPI2 regulates cell proliferation, inflammation, and extracellular matrix (ECM) remodeling, preserving tissue homeostasis. TFPI2 also regulates vascular endothelial and smooth muscle cell proliferation, key elements of the tumor microenvironment (TME). In the nucleus, it may modulate transcription factors to influence tumor-associated macrophage (TAM) polarization, facilitating cancer invasion. Its expression may be shaped by interactions between cancer cells and TAM activation. Beyond tumorigenesis, TFPI2 contributes to both inflammatory progression and resolution in diabetes, atherosclerosis, and preeclampsia. CONCLUSIONS TFPI2 may interact with TAMs and inflammatory cells to regulate cell proliferation and inflammation, maintaining tissue homeostasis.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan;
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
- Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, 3-3-17 Kitatomigaoka-cho, Nara 634-0001, Japan
| | - Shogo Imanaka
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan;
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
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Wu Q, Zhang X, Qin M, Shi D, Li Y. Dual roles of LncRNA RNA143598: a biomarker for rheumatoid arthritis and its implications in cancer. Clin Rheumatol 2025:10.1007/s10067-025-07448-2. [PMID: 40279008 DOI: 10.1007/s10067-025-07448-2] [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: 11/29/2024] [Revised: 02/24/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
OBJECTIVE Rheumatoid arthritis (RA) is a chronic autoimmune disease with complex pathological mechanisms, including immune system dysregulation and chronic inflammation. Recent studies indicate that long non-coding RNAs (LncRNAs) play key roles in immune regulation and have been implicated in the pathogenesis of multiple diseases, including RA and various types of cancer. Understanding the involvement of LncRNAs in RA and their potential transcriptional effects in cancer could provide novel insights into disease mechanisms and therapeutic targets. METHODS Using the GSE94519 dataset, we analyzed serum LncRNA profiles from RA patients and healthy controls. Differential expression genes (DEGs) were identified using GEO2R, and findings were validated via quantitative polymerase chain reaction (qPCR) in 39 RA and 53 healthy samples. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance. A pan-cancer analysis of MTRNR2L1 was conducted using TCGA data, with immune infiltration assessed via ssGSEA. RESULTS RNA143598 was significantly upregulated in RA patients, and qPCR confirmed its diagnostic potential (AUC = 0.77). Pan cancer analysis shows that MTRNR2L1 is highly expressed in glioblastoma (GBM) and lowly expressed in head and neck squamous cell carcinoma (HNSC), with high GBM expression linked to poor prognosis. Immune infiltration analysis showed MTRNR2L1 correlated with CD8 + T cells, macrophages, and dendritic cells in GBM. CONCLUSION RNA143598 is a promising RA biomarker, and its transcription gene MTRNR2L1 demonstrates potential in cancer prognosis and immune regulation. These findings provide a foundation for future research on targeted therapies for RA and cancer. Key Points • RNA143598 is identified as a significant biomarker for diagnosing rheumatoid arthritis (RA), showing promise for clinical application. • Quantitative PCR validation demonstrates the diagnostic potential of RNA143598, with an area under the curve (AUC) of 0.77. • MTRNR2L1, which is RNA143598 transcribed gene, exhibits differential expression in different cancer types, with high levels associated with poor prognosis in glioblastoma (GBM). • Immune infiltration analysis links MTRNR2L1 expression to the presence of CD8 + T cells, macrophages, and dendritic cells, suggesting its role in immune regulation in GBM.
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Affiliation(s)
- Qiuhua Wu
- Department of Clinical Laboratory, First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou City, Huzhou, 313000, Zhejiang, China
| | - Xiaoxia Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou City, Huzhou, 313000, Zhejiang, China
| | - Meiyun Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou City, Huzhou, 313000, Zhejiang, China
| | - Danfei Shi
- Department of Pathology, First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou City, Huzhou, 313000, Zhejiang, China
| | - Yong Li
- Department of Clinical Laboratory, First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou City, Huzhou, 313000, Zhejiang, China.
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30
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Liu H, Wang G, Li Z, Zhang X, Zhang W, Zhang X, Liu F, Gao J. Exosome-based immunotherapy in hepatocellular carcinoma. Clin Exp Med 2025; 25:127. [PMID: 40274634 PMCID: PMC12021721 DOI: 10.1007/s10238-025-01659-2] [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: 02/13/2025] [Accepted: 03/29/2025] [Indexed: 04/26/2025]
Abstract
Hepatocellular carcinoma (HCC) is a significant global health concern and ranks as the third leading cause of cancer-associated mortality. Systemic therapy faces the emergence of resistance, which hinders the clinical benefits. Recent evidence suggests that exosomes, measuring between 30 and 150 nm in size, which impact the antitumor immune responses, making them a promising candidate for cancer immunotherapy. Owing to their unique physical and chemical characteristics, exosomes can be tailored and engineered for a range of therapeutic objectives. In the present review, we outline the immunomodulatory functions of exosomes in the tumor microenvironment (TME) of HCC, aiming to decipher the underlying mechanisms of exosomes in remodeling suppressive TME. Moreover, we provide detailed and intuitive resource for leveraging the potential of exosomes in immunotherapy, presenting valuable strategies to improve and optimize HCC treatment. Despite the huge therapeutic potential of exosomes, significant challenges persist, including the need for standardization in exosome production, optimization of cargo loading techniques, and the assurance of safety and effectiveness in clinical applications. Addressing these challenges may pave the way for exosome-based immunotherapy for HCC patients.
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Affiliation(s)
- Hong Liu
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - GuoWei Wang
- Department of Radiology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - ZhaoYi Li
- Department of Scientific Research and Education, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - XianTu Zhang
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - WeiDong Zhang
- Department of General Surgery I, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - Xia Zhang
- Medical Laboratory, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
| | - Fang Liu
- Xixi Hospital Biobank, Xixi Hospital of Hangzhou, Zhejiang Province, Hangzhou, 310023, China.
| | - Jing Gao
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
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He Y, Liu Q, Luo Z, Hu Q, Wang L, Guo Z. Role of Tumor-Associated Macrophages in Breast Cancer Immunotherapy. FRONT BIOSCI-LANDMRK 2025; 30:26995. [PMID: 40302326 DOI: 10.31083/fbl26995] [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: 10/16/2024] [Revised: 12/04/2024] [Accepted: 12/11/2024] [Indexed: 05/02/2025]
Abstract
Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.
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Affiliation(s)
- Yan He
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Quan Liu
- Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, 518052 Shenzhen, Guangdong, China
| | - Zhihao Luo
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Qian Hu
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Li Wang
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Zifen Guo
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
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Esmaeilzadeh A, Hadiloo K, Yaghoubi S, Makoui MH, Mostanadi P. State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01056-7. [PMID: 40261561 DOI: 10.1007/s13402-025-01056-7] [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: 01/24/2025] [Accepted: 03/19/2025] [Indexed: 04/24/2025] Open
Abstract
Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain to the production of the drugs, solid tumor resistance, and side effects related to the treatment. Some cases have been missed during the drug preparation due to manufacturing issues, prolonged production times, and high costs. These challenges mainly arise from the in vitro manufacturing process, so reevaluating this process could minimize the number of missed patients. The immune cells are traditionally collected and sent to the laboratory; after several steps, the cells are modified to express the CAR gene before being injected back into the patient's body. During the in vivo method, the CAR gene is introduced to the immune cells inside the body. This allows for treatment to begin sooner, avoiding potential failures in drug preparation and the associated high costs. In this review, we will elaborate on the production and treatment process using in vivo CAR, examine the benefits and challenges of this approach, and ultimately present the available solutions for incorporating this treatment into clinical practice.
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Affiliation(s)
- Abdolreza Esmaeilzadeh
- Pficell R&D Canadian Institution & Corporation, Profound Future Focused Innovative Cell and Gene Therapy, Pficell Canadian Institution and Corporation, Ontario, Canada.
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Kaveh Hadiloo
- Pficell R&D Canadian Institution & Corporation, Profound Future Focused Innovative Cell and Gene Therapy, Pficell Canadian Institution and Corporation, Ontario, Canada
- Department of Surgery, Velayat Clinical Research Development Unit, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
| | - Sara Yaghoubi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Parsa Mostanadi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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Xu C, Chen J, Tan M, Tan Q. The role of macrophage polarization in ovarian cancer: from molecular mechanism to therapeutic potentials. Front Immunol 2025; 16:1543096. [PMID: 40330466 PMCID: PMC12052780 DOI: 10.3389/fimmu.2025.1543096] [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: 12/10/2024] [Accepted: 03/21/2025] [Indexed: 05/08/2025] Open
Abstract
Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC's aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.
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Affiliation(s)
| | | | | | - Qingqing Tan
- Department of Gynecology and Obstetrics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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Liu N, Wang X, Wang Z, Kan Y, Fang Y, Gao J, Kong X, Wang J. Nanomaterials-driven in situ vaccination: a novel frontier in tumor immunotherapy. J Hematol Oncol 2025; 18:45. [PMID: 40247328 PMCID: PMC12007348 DOI: 10.1186/s13045-025-01692-4] [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: 10/09/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.
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Affiliation(s)
- Naimeng Liu
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiangyu Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yonemori Kan
- Department of Medical Oncology, National Cancer Center Hospital (NCCH), 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jidong Gao
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518127, China.
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Adamecz DI, Veres É, Papp C, Árva H, Rónavári A, Marton A, Vizler C, Gácser A, Kónya Z, Igaz N, Kiricsi M. Gold and Silver Nanoparticles Efficiently Modulate the Crosstalk Between Macrophages and Cancer Cells. Int J Nanomedicine 2025; 20:4777-4802. [PMID: 40255669 PMCID: PMC12009049 DOI: 10.2147/ijn.s508171] [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: 12/10/2024] [Accepted: 04/02/2025] [Indexed: 04/22/2025] Open
Abstract
Background Macrophages, polarized into pro-inflammatory M1 or anti-inflammatory M2 states, are essential cellular elements of innate immunity. In the tumor microenvironment, owing to a paracrine manipulative program by cancerous cells, tumor-associated macrophages (TAMs) evolve, which can shift between M1-like and M2-like phenotypes. Since it is fairly unknown how the promising anticancer agents, silver (AgNPs) and gold nanoparticles (AuNPs) affect the bidirectional communication and reprogramming in the tumor stroma, we examined the behavior, the tumor-supporting functions, and the expression of polarization and functional marker genes of TAMs to reveal how these are modulated upon interaction with nanoparticle-exposed cancer cells. Methods We established co-cultures of murine immortalized J774 or primary bone marrow-derived macrophages with 4T1 breast cancer cells treated with AuNPs or AgNPs or with none of the nanoparticles. We assessed the expression of macrophage polarization and functional markers using RT-qPCR and Proteome Profiler Array and evaluated macrophage migration and matrix metalloproteinase activity by specific assays. Results Protein and mRNA levels of most examined factors - except tumor necrosis factor-alpha - such as C-C-motif chemokine ligands 2 and 22, interleukin-23, inducible nitric oxide synthase, cyclooxygenase-2, the macrophage mannose receptor CD206, transforming growth factor-beta, and chitinase-like-3 protein decreased, and the expression of polarization markers revealed a shift towards M1-like phenotype in macrophages co-cultured with AgNP- or AuNP-treated 4T1 cells. Both nanoparticle treatments reduced the levels and activity of cell migration-related factors, such as C-C motif chemokine ligand 3, matrix metalloproteinases, and suppressed macrophage migration. Conclusion Both AuNPs and AgNPs showed a remarkable ability to influence macrophage-cancer cell communication, suppressed indirectly M2-like TAM polarization, and perturbed the migration behavior of TAMs that is critical for tumor invasion, indicating modulated immunological functions and debilitated cancer-promoting capabilities of TAMs in this microenvironment.
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Affiliation(s)
- Dóra Izabella Adamecz
- Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
- Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Éva Veres
- Doctoral School of Biology, University of Szeged, Szeged, Hungary
- Department of Biotechnology and Microbiology, University of Szeged, Szeged, Hungary
- HCEMM-SZTE Pathogen Fungi Research Group, University of Szeged, Szeged, Hungary
| | - Csaba Papp
- Department of Biotechnology and Microbiology, University of Szeged, Szeged, Hungary
- HCEMM-SZTE Pathogen Fungi Research Group, University of Szeged, Szeged, Hungary
| | - Hédi Árva
- Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
- Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Andrea Rónavári
- Department of Applied and Environmental Chemistry, University of Szeged, Szeged, Hungary
| | - Annamária Marton
- Laboratory of Tumor Immunology and Pharmacology, Centre of Excellence of the European Union, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Csaba Vizler
- Laboratory of Tumor Immunology and Pharmacology, Centre of Excellence of the European Union, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Attila Gácser
- Department of Biotechnology and Microbiology, University of Szeged, Szeged, Hungary
- HCEMM-SZTE Pathogen Fungi Research Group, University of Szeged, Szeged, Hungary
| | - Zoltán Kónya
- Department of Applied and Environmental Chemistry, University of Szeged, Szeged, Hungary
| | - Nóra Igaz
- Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
| | - Mónika Kiricsi
- Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
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Rothe R, Golle T, Hachkar B, Hörz T, Pablik J, Rupp L, Dietsche I, Kruppa C, Fitze G, Schmitz M, Haase M, Wehner R. Tertiary Lymphoid Structures Are Associated with Progression-Free Survival of Peripheral Neuroblastic Tumor Patients. Cancers (Basel) 2025; 17:1303. [PMID: 40282480 PMCID: PMC12025499 DOI: 10.3390/cancers17081303] [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: 02/27/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Peripheral neuroblastic tumors (pNT) are a biologically heterogeneous group of embryonal tumors that derive from the neural crest and affect the sympathetic nervous system. So far, little is known about the complex immune landscape in these rare childhood cancers. Methods: We focused on the immune cell infiltrate of treatment-naïve pNT from 24 patients, including high-risk neuroblastoma (HR-NBL), non-high-risk neuroblastoma (NHR-NBL), ganglioneuroblastoma (GNBL), and rare ganglioneuroma (GN). To gain novel insights into the immune architecture of these pNT subtypes, we used multiplex immunohistochemistry, multispectral imaging, and algorithm-based data evaluation to detect and characterize T cells, B cells, neutrophils, macrophages, and tertiary lymphoid structures (TLS). Results: The majority of the investigated tumor-infiltrating immune cells were macrophages and T cells. Their detailed phenotypic characterization revealed high proportions of M2-like macrophages as well as activated GrzB+ CD8+ and PD-1+ T lymphocytes. Proportions of these T cell phenotypes were significantly increased in GN compared to HR-NBL, NHR-NBL, or GNBL. In addition, TLS occurred in 11 of 24 patients, independent of immune cell frequencies in the whole tissues. Interestingly, all GN, most GNBL, but only a few NBL contained TLS. We distinguished between three TLS maturation stages that were present irrespective of the pNT subtype. The majority belonged to mature TLS of the primary follicle state. Mature LAMP3+ dendritic cells were also found, predominantly in T cell zones of TLS. Furthermore, TLS presence identified pNT patients with significantly prolonged progression-free survival in contrast to all other analyzed immunological features. Conclusions: We propose TLS to be a potential prognostic marker for pNT to predict patient outcomes.
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Affiliation(s)
- Rebecca Rothe
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
- National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- German Cancer Consortium (DKTK), 01307 Dresden, Germany
| | - Therés Golle
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
| | - Basma Hachkar
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
| | - Tina Hörz
- Department of Pediatric Surgery, University Hospital Carl Gustav Carus, 01307 Dresden, Germany; (T.H.); (C.K.); (G.F.); (M.H.)
| | - Jessica Pablik
- Department of Pathology, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;
| | - Luise Rupp
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
| | - Ina Dietsche
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
| | - Christian Kruppa
- Department of Pediatric Surgery, University Hospital Carl Gustav Carus, 01307 Dresden, Germany; (T.H.); (C.K.); (G.F.); (M.H.)
| | - Guido Fitze
- Department of Pediatric Surgery, University Hospital Carl Gustav Carus, 01307 Dresden, Germany; (T.H.); (C.K.); (G.F.); (M.H.)
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
- National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- German Cancer Consortium (DKTK), 01307 Dresden, Germany
| | - Michael Haase
- Department of Pediatric Surgery, University Hospital Carl Gustav Carus, 01307 Dresden, Germany; (T.H.); (C.K.); (G.F.); (M.H.)
| | - Rebekka Wehner
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany; (R.R.); (T.G.); (B.H.); (L.R.); (I.D.); (M.S.)
- National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- German Cancer Consortium (DKTK), 01307 Dresden, Germany
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Tang J, Chen L, Shen X, Xia T, Li Z, Chai X, Huang Y, Yang S, Peng X, Lai J, Li R, Xie L. Exploring the Role of Cellular Interactions in the Colorectal Cancer Microenvironment. J Immunol Res 2025; 2025:4109934. [PMID: 40255905 PMCID: PMC12008489 DOI: 10.1155/jimr/4109934] [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: 08/23/2024] [Accepted: 02/22/2025] [Indexed: 04/22/2025] Open
Abstract
Colorectal cancer (CRC) stands as one of the tumors with globally high incidence and mortality rates. In recent years, researchers have extensively explored the role of the tumor immune microenvironment (TME) in CRC, highlighting the crucial influence of immune cell populations in driving tumor progression and shaping therapeutic outcomes. The TME encompasses an array of cellular and noncellular constituents, spanning tumor cells, immune cells, myeloid cells, and tumor-associated fibroblasts, among others. However, the cellular composition within the TME is highly dynamic, evolving throughout different stages of tumor progression. These shifts in cell subpopulation proportions lead to a gradual transition in the immune response, shifting from an early antitumor growth to a late-stage environment that supports tumor survival. Therefore, it is crucial to further investigate and understand the complex interactions among the various cell populations within the TME. In this review, we explore the key cellular components of varying origins, subpopulations with shared origins, and noncellular elements within the CRC TME, examining their interconnections and critical considerations for developing personalized and precise immunotherapy strategies.
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Affiliation(s)
- Jiadai Tang
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Liuhan Chen
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Xin Shen
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Tingrong Xia
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Zhengting Li
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Xiaoying Chai
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Yao Huang
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Shaoqiong Yang
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Xinjun Peng
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Junbo Lai
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Rui Li
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
| | - Lin Xie
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China
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Brumfield GL, Knoche SM, Doty KR, Larson AC, Poelaert BJ, Coulter DW, Solheim JC. Amyloid precursor-like protein 2 expression in macrophages: differentiation and M1/M2 macrophage dynamics. Front Oncol 2025; 15:1570955. [PMID: 40265027 PMCID: PMC12011594 DOI: 10.3389/fonc.2025.1570955] [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: 02/04/2025] [Accepted: 03/13/2025] [Indexed: 04/24/2025] Open
Abstract
Amyloid precursor-like protein 2 (APLP2) has been previously associated with pro-tumor phenotypes in cancer cells, and in this current study we investigated the expression and functions of this protein in macrophages. Our findings showed that APLP2 expression was increased in monocyte-like U937 cells after cytokine-induced differentiation to macrophage-like cells. Evaluation of human mRNA data revealed that APLP2 is more highly expressed in human M2/anti-inflammatory (pro-tumor) macrophages than in M1 macrophages (which have a pro-inflammatory, anti-tumor phenotype). Consistent with the mRNA data, by immunoblotting we identified increased APLP2 protein expression in mouse M2/anti-inflammatory macrophages. Intratumoral infiltration of M2/anti-inflammatory macrophages has been reported in several cancers, including neuroblastoma (NB). We observed that treatment of macrophages with NB-conditioned media induced M2/anti-inflammatory and mixed phenotypes. Through comparison of macrophages from wild-type and APLP2-knockout mice, we correlated alterations in inflammation-associated markers with the presence of APLP2. This suggests that APLP2 influences macrophage polarization dynamics between M0/unpolarized and pro- and anti-inflammatory states, and populations altered by APLP2 KO resemble the macrophage profiles altered with NB-conditioned media treatment. In total, our work implicates APLP2 as a mediator of macrophage status, namely in the M0/unpolarized macrophage and the M1/pro-inflammatory and M2/anti-inflammatory axis.
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Affiliation(s)
- Gabrielle L. Brumfield
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Shelby M. Knoche
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kenadie R. Doty
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Alaina C. Larson
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Brittany J. Poelaert
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Don W. Coulter
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, United States
- Children's Nebraska, Omaha, NE, United States
| | - Joyce C. Solheim
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
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Bai T, Li P, Liu Y, Cai B, Li G, Wang W, Yan R, Zheng X, Du S. Knockdown of miR-411-3p induces M2 macrophage polarization and promotes colorectal cancer progression by regulation of MMP7. Eur J Histochem 2025; 69:4178. [PMID: 40322788 PMCID: PMC12086358 DOI: 10.4081/ejh.2025.4178] [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: 12/26/2024] [Accepted: 04/13/2025] [Indexed: 05/21/2025] Open
Abstract
Colorectal cancer (CRC) is prone to metastasis, leading to a poor prognosis. miR-411-3p exhibits a tumor-suppressive function in CRC, but its exact mechanism is unclear. The malignant biological properties of CRC cells were detected by Carboxyfluorescein diacetate succinimidyl ester (CFSE) staining, scratch-wound and transwell assay. Levels of markers associated with macrophage polarization were evaluated by flow cytometry and ELISA kits. Bioinformatics analysis to screen whether the downstream target mRNA of miR-411-3p is matrix metalloproteinase 7 (MMP7), and Dual-Luciferase reporter assay verified the targeting relationship between the two. qRT-PCR tested miR-411-3p and MMP7 levels. MMP7 level was quantified by Western blot. Additionally, a nude mouse subcutaneous graft tumor model was constructed, Ki-67 expression was detected by immunohistochemistry, and the impact of miR-411-3p/MMP7 on the polarization of M2 macrophages was explored. miR-411-3p expression is downregulated in CRC. Knockdown of miR-411-3p elevated the amount of CFSE-positive, migrating, and invading cells, decreased apoptosis, and elevated the levels of M2 macrophage polarization markers. After overexpression of miR-411-3p, all of the above metrics were reversed in CRC cells. miR-411-3p targeted negative regulation of MMP7 expression, and MMP7 overexpression further enhanced the promotional effect of knockdown of miR-411-3p on the malignant progression of CRC and M2 macrophage polarization. Furthermore, knockdown of miR-411-3p upregulated the MMP7 level, elevated Ki-67-positive cells count, and induced M2 macrophage polarization in vivo. Knockdown of miR-411-3p upregulates MMP7 and induces M2 macrophage polarization, which in turn promotes malignant biological progression of CRC.
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Affiliation(s)
- Tianliang Bai
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Ping Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Yabin Liu
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Hebei Province
| | - Bindan Cai
- Department of Neurology, Zhuozhou City Hospital, Hebei Province, China
| | - Gang Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Wenbin Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Rui Yan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Xiangkui Zheng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
| | - Shangkun Du
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province
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Mielcarska S, Kot A, Kula A, Dawidowicz M, Sobków P, Kłaczka D, Waniczek D, Świętochowska E. B7H3 in Gastrointestinal Tumors: Role in Immune Modulation and Cancer Progression: A Review of the Literature. Cells 2025; 14:530. [PMID: 40214484 PMCID: PMC11988818 DOI: 10.3390/cells14070530] [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: 03/11/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
B7-H3 (CD276), a member of the B7 immune checkpoint family, plays a critical role in modulating immune responses and has emerged as a promising target in cancer therapy. It is highly expressed in various malignancies, where it promotes tumor evasion from T cell surveillance and contributes to cancer progression, metastasis, and therapeutic resistance, showing a correlation with the poor prognosis of patients. Although its receptors were not fully identified, B7-H3 signaling involves key intracellular pathways, including JAK/STAT, NF-κB, PI3K/Akt, and MAPK, driving processes crucial for supporting tumor growth such as cell proliferation, invasion, and apoptosis inhibition. Beyond immune modulation, B7-H3 influences cancer cell metabolism, angiogenesis, and epithelial-to-mesenchymal transition, further exacerbating tumor aggressiveness. The development of B7-H3-targeting therapies, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cells, offers promising avenues for treatment. This review provides an up-to-date summary of the B7H3 mechanisms of action, putative receptors, and ongoing clinical trials evaluating therapies targeting B7H3, focusing on the molecule's role in gastrointestinal tumors.
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Affiliation(s)
- Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Piotr Sobków
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Daria Kłaczka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
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Wei W, Li J, Huang J, Jiang Q, Lin C, Hu R, Wei J, Li Q, Xu G, Chang Z. Exosomal miR‑3681‑3p from M2‑polarized macrophages confers cisplatin resistance to gastric cancer cells by targeting MLH1. Mol Med Rep 2025; 31:94. [PMID: 39981936 PMCID: PMC11851060 DOI: 10.3892/mmr.2025.13459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/07/2025] [Indexed: 02/22/2025] Open
Abstract
Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2‑polarized macrophages, which promote this resistance, on the response of gastric cancer cells to DDP, examining both the effects and the underlying mechanisms. M2 macrophages, differentiated from mouse bone marrow cells with interleukin (IL)‑13 and IL‑4, were identified using immunofluorescence staining for CD206 and CD163. Exosomes derived from these macrophages were characterized using transmission electron microscopy and protein markers, including calnexin, tumor susceptibility gene 101 and CD9. The role of exosomal microRNA (miR)‑3681‑3p in DDP resistance was assessed using Cell Counting Kit‑8 and apoptosis assays, while a luciferase reporter assay was used to elucidate the interaction between miR‑3681‑3p and MutL protein homolog 1 (MLH1). Co‑culturing gastric cancer cells with M2 macrophages enhanced DDP resistance, an effect amplified by exosomes from M2 macrophages enriched with miR‑3681‑3p. This microRNA directly targeted and reduced MLH1 protein expression. Overexpression of miR‑3681‑3p through mimic transfection, along with MLH1 silencing by small interfering RNA transfection, significantly increased DDP resistance, as evidenced by elevated IC50 values in AGS cells. By contrast, the overexpression of MLH1 effectively reversed the drug resistance of AGS cells to DDP caused by miR‑3681‑3p mimic transfection, as evidenced by a decrease in the IC50 value. In conclusion, exosomal miR‑3681‑3p from M2 macrophages may have a key role in conferring DDP resistance to gastric cancer by suppressing MLH1, offering a new therapeutic target for overcoming chemoresistance.
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Affiliation(s)
- Wujun Wei
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jiaxing Li
- Department of Pharmacy, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jingjing Huang
- Department of Health Care, Baise Maternity and Child Health Center, Baise, Guangxi 533000, P.R. China
| | - Qi Jiang
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Cheng Lin
- Department of Oncology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Rentong Hu
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jiazhu Wei
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Qiao Li
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Guidan Xu
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Zhengyi Chang
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
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El-Shiekh RA, Atwa AM, Elgindy AM, Ibrahim KM, Senna MM, Ebid N, Mustafa AM. Current Perspective and Mechanistic Insights on α-Hederin for the Prevention and Treatment of Several Noncommunicable Diseases. Chem Biodivers 2025; 22:e202402289. [PMID: 39607970 DOI: 10.1002/cbdv.202402289] [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: 09/13/2024] [Revised: 11/12/2024] [Accepted: 11/28/2024] [Indexed: 11/30/2024]
Abstract
α-Hederin, a naturally occurring compound found in various plant sources, has remarkable properties and therapeutic potential for human health. One notable attribute is its potent anti-inflammatory activity, such as in arthritis, asthma, and inflammatory bowel disease. In addition, it exhibits notable antioxidant effects implicated in the development of chronic diseases, including cardiovascular disorders and certain types of cancer. According to research, it may limit the growth and proliferation of cancer cells, making it a possible candidate for future cancer treatments. Moreover, it is a promising neuroprotective agent and enhances cognitive function, suggesting its potential in the treatment of neurodegenerative illnesses like Alzheimer's and Parkinson's disease. The multifaceted benefits of α-hederin make it an intriguing compound with significant therapeutic implications. As research progresses, exploring its mechanisms of action and clinical applications is warranted. Harnessing the potential of α-hederin may pave the way for innovative treatment strategies and improved outcomes in the battle against various chronic diseases.
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Affiliation(s)
- Riham A El-Shiekh
- Faculty of Pharmacy, Department of Pharmacognosy, Cairo University, Cairo, Egypt
| | - Ahmed M Atwa
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Ayen Iraqi University, Thi-Qar, Iraq
| | - Ali M Elgindy
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Kawther Magdy Ibrahim
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Mohamed Magdy Senna
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Nouran Ebid
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Aya M Mustafa
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
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43
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Zou B, Wang M, Bai S, Li N, Fan Z, Peng Y, Han M, Zeng C, Lu H, Qi L, Zhang X, Tan X, Liao Q. Novel mRNA-Engineered Fully Human CAR-T Cells Targeting AXL in Solid Tumors. Biomedicines 2025; 13:844. [PMID: 40299452 PMCID: PMC12024984 DOI: 10.3390/biomedicines13040844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/26/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Background/Objectives: The AXL receptor tyrosine kinase is a promising therapeutic target in solid tumors, yet conventional viral vector-engineered CAR-T cells face critical limitations, including risks of insertional mutagenesis and immunogenicity from murine-derived single-chain variable fragments (scFvs). This study aimed to develop and evaluate mRNA-engineered fully human AXL CAR-T (mfhAXL CAR-T) cells as a safer, scalable alternative for solid tumor immunotherapy. Methods:mfhAXL CAR-T cells were generated via electroporation-mediated delivery of in vitro transcribed mRNA encoding a fully human AXL-specific CAR. CAR expression kinetics and T-cell viability were quantified by flow cytometry. Antitumor activity was assessed through in vitro co-cultures with AXL-positive lung and pancreatic cancer cells, measuring cytotoxicity, cytokine secretion, and specificity. In vivo efficacy was evaluated in a lung cancer xenograft mouse model, with tumor volume and body weight monitored over 14 days. Results: Flow cytometry confirmed transient but high CAR expression (>90% at 24 h) with preserved T-cell viability (>90%). In vitro, mfhAXL CAR-T cells exhibited dose-dependent cytotoxicity and antigen-specific cytokine secretion. In vivo, four administrations of mfhAXL CAR-T cells suppressed tumor growth without body weight loss. Conclusions: The mRNA-electroporated mfhAXL CAR-T platform enables cost-effective, large-scale production, offering a safer alternative to viral vector-based approaches by eliminating risks of insertional mutagenesis and immunogenicity.
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Affiliation(s)
- Bo Zou
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen Campus, Shenzhen 518106, China (L.Q.)
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Mengge Wang
- Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; (M.W.); (C.Z.)
| | - Shimeng Bai
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Ning Li
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Zhongyi Fan
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Yuanzheng Peng
- Kidney Transplant Department (Liver Transplant Department), Transplant Center, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China;
| | - Mingshu Han
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Chen Zeng
- Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; (M.W.); (C.Z.)
| | - Hongzhou Lu
- National Clinical Research Centre for Infectious Diseases, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China;
| | - Lin Qi
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen Campus, Shenzhen 518106, China (L.Q.)
| | - Xingding Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen Campus, Shenzhen 518106, China (L.Q.)
| | - Xiaohua Tan
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
| | - Qibin Liao
- Biotherapy Clinical Research Center, Shenzhen Third People’s Hospital, The Second Affiliated Hospital to Southern University of Science and Technology, Shenzhen 518112, China; (S.B.); (N.L.); (Z.F.); (M.H.); (X.T.)
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Zhu W, Yang Z, Zhou S, Zhang J, Xu Z, Xiong W, Liu P. Modic changes: From potential molecular mechanisms to future research directions (Review). Mol Med Rep 2025; 31:90. [PMID: 39918002 PMCID: PMC11836598 DOI: 10.3892/mmr.2025.13455] [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: 10/09/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Low back pain (LBP) is a leading cause of disability worldwide. Although not all patients with Modic changes (MCs) experience LBP, MC is often closely associated with LBP and disc degeneration. In clinical practice, the focus is usually on symptoms related to MC, which are hypothesized to be associated with LBP; however, the link between MC and nerve compression remains unclear. In cases of intervertebral disc herniation, nerve compression is often the definitive cause of symptoms. Recent advances have shed light on the pathophysiology of MC, partially elucidating its underlying mechanisms. The pathogenesis of MC involves complex bone marrow‑disc interactions, resulting in bone marrow inflammation and edema. Over time, hematopoietic cells are gradually replaced by adipocytes, ultimately resulting in localized bone marrow sclerosis. This process creates a barrier between the intervertebral disc and the bone marrow, thereby enhancing the stability of the vertebral body. The latest understanding of the pathophysiology of MC suggests that chronic inflammation plays a significant role in its development and hypothesizes that the complement system may contribute to its pathological progression. However, this hypothesis requires further research to be confirmed. The present review we proposed a pathological model based on current research, encompassing the transition from Modic type 1 changes (MC1) to Modic type 2 changes (MC2). It discussed key cellular functions and their alterations in the pathogenesis of MC and outlined potential future research directions to further elucidate its mechanisms. Additionally, it reviewed the current clinical staging and pathogenesis of MC, recommended the development of an updated staging system and explored the prospects of integrating emerging artificial intelligence technologies.
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Affiliation(s)
- Weijian Zhu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhou Yang
- Department of Orthopedics, Hongxin Harmony Hospital, Li Chuan, Hubei 445400 P.R. China
| | - Sirui Zhou
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
| | - Jinming Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhihao Xu
- Department of Hepatobiliary Surgery, Huaqiao Hospital, Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Wei Xiong
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ping Liu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
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45
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Liu L, Luo H, Xie Y, Wang Y, Ren S, Sun H, Li D. IL-33/ST2 signalling promotes tumor growth by regulating polarization of alternatively activated macrophages. Cancer Biol Med 2025; 22:j.issn.2095-3941.2024.0483. [PMID: 40145895 PMCID: PMC12032832 DOI: 10.20892/j.issn.2095-3941.2024.0483] [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: 10/26/2024] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
OBJECTIVE Suppression of tumorigenicity 2 (ST2), the receptor for interleukin (IL)-33, has a critical role in tumor growth, angiogenesis, metastasis, and immune modulation. The IL-33/ST2 pathway is known to influence the polarization and function of macrophages, which is integral to modulating the tumor microenvironment. However, the precise role of IL-33/ST2 in tumors, particularly non-small cell lung cancer (NSCLC), has not been established. METHODS ST2 expression in NSCLC was analysed using a murine model and patient specimens. The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined. RESULTS Elevated ST2 expression was correlated with aggressive tumor growth. Specifically, ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth. IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway. Moreover, IL-33 inhibited T-cell function by inducing the secretion of transforming growth factor β from alternatively activated macrophages. CONCLUSIONS Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy, highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.
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Affiliation(s)
- Liping Liu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Haoge Luo
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Yingdong Xie
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Ying Wang
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Shiying Ren
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Haiyang Sun
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Dong Li
- Key Laboratory of Pathobiology, Ministry of Education, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
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46
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Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, Zhao LJ. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol 2025; 16:1563303. [PMID: 40207222 PMCID: PMC11979165 DOI: 10.3389/fimmu.2025.1563303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Lai
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Dan Tang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Hepatobiliary and Pancreatic Surgery, Suzhou Medical College of Soochow University, Suzhou, China
| | - Long Hu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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47
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Chen X, Tang X, Xie Y, Cuffari BJ, Tang C, Cao F, Gao X, Meng Z, Noble PW, Young MR, Turk OM, Shirali A, Gera J, Nishimura RN, Zhou J, Hansen JE. A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells. Sci Signal 2025; 18:eadk3320. [PMID: 40132052 PMCID: PMC12076517 DOI: 10.1126/scisignal.adk3320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/27/2024] [Accepted: 02/21/2025] [Indexed: 03/27/2025]
Abstract
Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.
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Affiliation(s)
- Xiaoyong Chen
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Xiangjun Tang
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520
| | - Ying Xie
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520
| | - Benedette J. Cuffari
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Caroline Tang
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Fei Cao
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Xingchun Gao
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520
| | - Zhouqi Meng
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520
| | - Philip W. Noble
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Melissa R. Young
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520
| | - Olivia M. Turk
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Anupama Shirali
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
| | - Joseph Gera
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095
- Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095
- Molecular Biology Institute, UCLA, Los Angeles, CA, 90095
- Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343
| | - Robert N. Nishimura
- Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343
- Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, CA, 90095
| | - Jiangbing Zhou
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520
| | - James E. Hansen
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520
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Zhao T, Luo Y, Sun Y, Wei Z. Characterizing macrophage diversity in colorectal malignancies through single-cell genomics. Front Immunol 2025; 16:1526668. [PMID: 40191203 PMCID: PMC11968368 DOI: 10.3389/fimmu.2025.1526668] [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: 11/12/2024] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract, with increasing incidence and mortality rates, posing a significant burden on human health. Its progression relies on various mechanisms, among which the tumor microenvironment and tumor-associated macrophages (TAMs) have garnered increasing attention. Macrophage infiltration in various solid tumors is associated with poor prognosis and is linked to chemotherapy resistance in many cancers. These significant biological behaviors depend on the heterogeneity of macrophages. Tumor-promoting TAMs comprise subpopulations characterized by distinct markers and unique transcriptional profiles, rendering them potential targets for anticancer therapies through either depletion or reprogramming from a pro-tumoral to an anti-tumoral state. Single-cell RNA sequencing technology has significantly enhanced our research resolution, breaking the traditional simplistic definitions of macrophage subtypes and deepening our understanding of the diversity within TAMs. However, a unified elucidation of the nomenclature and molecular characteristics associated with this diversity remains lacking. In this review, we assess the application of conventional macrophage polarization subtypes in colorectal malignancies and explore several unique subtypes defined from a single-cell omics perspective in recent years, categorizing them based on their potential functions.
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Affiliation(s)
- Tingshuo Zhao
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Yinyi Luo
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Yuanjie Sun
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Zhigang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Shanxi Medical University, Tai Yuan, China
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49
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Sholevar CJ, Liu NM, Mukarrama T, Kim J, Lawrence J, Canter RJ. Myeloid Cells in the Immunosuppressive Microenvironment as Immunotargets in Osteosarcoma. Immunotargets Ther 2025; 14:247-258. [PMID: 40125425 PMCID: PMC11930235 DOI: 10.2147/itt.s485672] [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: 12/31/2024] [Accepted: 03/11/2025] [Indexed: 03/25/2025] Open
Abstract
Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.
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Affiliation(s)
- Cyrus J Sholevar
- Department of Surgery, Division of Surgical Oncology, University of California Davis, Sacramento, CA, USA
| | - Natalie M Liu
- Department of Surgery, Division of Surgical Oncology, University of California Davis, Sacramento, CA, USA
| | - Tasneem Mukarrama
- Biomedical Engineering, University of California Davis, Sacramento, CA, USA
| | - Jinhwan Kim
- Biomedical Engineering, University of California Davis, Sacramento, CA, USA
| | - Jessica Lawrence
- Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Robert J Canter
- Department of Surgery, Division of Surgical Oncology, University of California Davis, Sacramento, CA, USA
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50
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Zhou X, Zhang Y, Huang B, Shi X, Bian M. Upregulated PXDNL promotes invasive breast carcinoma progression. Am J Transl Res 2025; 17:2154-2165. [PMID: 40225987 PMCID: PMC11982889 DOI: 10.62347/bouc4040] [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: 08/10/2024] [Accepted: 02/21/2025] [Indexed: 04/15/2025]
Abstract
BACKGROUND Invasive breast carcinoma (BRCA) is a common and serious malignancy in women. Peroxidase-like (PXDNL) is associated with poor prognosis in various cancers but has an unclear role in BRCA progression. METHODS Bioinformatic analysis of datasets from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and UALCAN investigated a potential carcinogenic role of PXDNL, focusing on its correlation with prognosis, promoter methylation, immune cell infiltration, immune checkpoint genes, and relevant biologic functions and pathways. RESULTS PXDNL demonstrated a significant expression profile in BRCA, with considerable diagnostic and prognostic implications. Its up-regulation correlated with decreased survival rates across various molecular subtypes of BRCA. Patients in the high PXDNL expression group showed reduced presence of multiple infiltrative immune cell types, including CD8+ T cells, cytotoxic cells, T cells, B cells, dendritic cells (DC), immature dendritic cells (iDC), natural killer (NK) cells, NK CD56bright cells, NK CD56dim cells, and follicular helper T cells (TFH). Additionally, a significant correlation was observed between PXDNL expression and immune checkpoint genes. Gene Set Enrichment Analysis (GSEA) further indicated that high PXDNL expression triggers pathways such as epithelial-mesenchymal transition and protein secretion, while suppressing crucial processes including allograft rejection, IL6-JAK-STAT3 signaling, TNFα signaling via NFκB, adipogenesis, oxidative phosphorylation, DNA repair, and the P53 pathway. CONCLUSION Overexpression of PXDNL is associated with poor prognosis and is linked to immune cell infiltration in BRCA. Thus, PXDNL may be a biomarker or therapeutic target for BRCA.
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Affiliation(s)
- Xianping Zhou
- Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical UniversityHefei, Anhui, The People’s Republic of China
- Department of Blood Transfusion, The People’s Hospital of BozhouBozhou, Anhui, The People’s Republic of China
| | - Yanqiu Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune MedicineHefei, Anhui, The People’s Republic of China
| | - Baoyu Huang
- Department of Gastrointestinal Surgery, The People’s Hospital of BozhouBozhou, Anhui, The People’s Republic of China
| | - Xiufang Shi
- Department of Clinical Laboratory, The People’s Hospital of BozhouBozhou, Anhui, The People’s Republic of China
| | - Maohong Bian
- Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical UniversityHefei, Anhui, The People’s Republic of China
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