International immunopharmacology最新文献

{"title":"IL-36R deletion mitigates cigarette smoke-induced airway inflammation and skeletal muscle dysfunction.","authors":"Danyang Li, Jingge Qu, Yuqiang Pei, Yafei Rao, Yue Zhang, Yahong Chen, Yongchang Sun","doi":"10.1016/j.intimp.2025.115317","DOIUrl":"10.1016/j.intimp.2025.115317","url":null,"abstract":"<p><p>Chronic inflammation is a crucial driver in the development of chronic obstructive pulmonary disease (COPD) and its comorbidities, such as skeletal muscle dysfunction. Heightened IL-36 expression in the lung and systemic circulation has been observed in patients with COPD, but the potential role of IL-36 in COPD still needs further exploration. Herein, we established a COPD model through long-term cigarette smoke (CS) exposure in mice with or without IL-36R deletion. Elevated IL-36 cytokines were observed in the lung and peripheral blood of CS-exposed wild-type mice. IL-36R gene deficiency attenuated CS-induced lung parenchymal destruction and airway inflammation, as evidenced by decreased secretion of inflammatory mediators, such as IL-6, IL-1β, TNF-α and MMP9, and a diminished Th1/Tc1- and Tfh-biased immune response. In addition, skeletal muscle dysfunction was alleviated in CS-exposed mice by IL-36R deletion. Further investigations indicated that CS treatment induced the expression of IL-36 cytokines and IL-36R in C2C12 myotubes and skeletal muscles, and that IL-36 cytokines could upregulate FBXO32 and TRIM63 expression by activating NF-κB p65 pathway, thereby leading to skeletal muscle atrophy in an endocrine and autocrine/paracrine manner. Our findings provide evidence for a critical role of the IL-36/IL-36R signaling in the pathogenesis of CS-induced COPD and comorbid skeletal muscle dysfunction.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115317"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico analysis of VEGFR2 and c-MET in consideration with immunologic facts: Implications for mRNA vaccine design against breast cancer.","authors":"Marziyeh Ghayoumian, Fahimeh Shamsi, Hamid Madanchi, Mohammad Mehdi Ranjbar, Reza Jalalirad, Ramin Sarrami Forooshani, Mehdi Mahdavi","doi":"10.1016/j.intimp.2025.115315","DOIUrl":"10.1016/j.intimp.2025.115315","url":null,"abstract":"<p><p>Active immunization in cancer therapy can induce tumor-specific immune responses without harming the normal cells. Among these approaches, especially after the success of FDA-approved mRNA vaccines, this platform has gained much more attention as a promising strategy. This study focused on designing an mRNA-based vaccine against breast cancer by selecting two angiogenic elements that are overexpressed in breast cancer cells, in an immunoinformatic approach. Epitopes were filtered based on antigenicity, toxicity, and allergenicity to ensure that they could elicit both T and B-cell-mediated immune responses. Molecular docking simulations analyzed their interactions with Major Histocompatibility Complex (MHC) molecules. The final vaccine construct included 10 selected epitopes linked with appropriate linkers and optimized for codon usage, ensuring ideal GC content and codon adaptation index. Protein docking analyses showed strong interactions with appropriate binding energies, while molecular dynamics simulations confirmed the docked complex stability. Immune simulations revealed high antibody titers, cytokine response, and an increase in immune cells such as B Cells, Cytotoxic T Lymphocyte (CTL) cells, and Helper T Lymphocyte (HTL) cells. Based on these findings, this vaccine design presents a strong candidate for an mRNA-based breast cancer vaccine, with further development currently underway.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115315"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein targets & therapeutics in psoriasis: toward personalization.","authors":"Mohammad Abuzar Shaikh, Ziyaul Haque, Anzarul Haque, Sanket Kumar, Mohamad Taleuzzaman","doi":"10.1016/j.intimp.2025.115331","DOIUrl":"10.1016/j.intimp.2025.115331","url":null,"abstract":"<p><p>Over 125 million individuals worldwide suffer from psoriasis, a chronic inflammatory skin condition that is immune-mediated. It is often linked to systemic comorbidities such psoriatic arthritis, cardiovascular disease, and mental health conditions. It is characterised by erythematous plaques, itching, and scaling. Psoriasis is caused by a complex interaction of environmental factors, genetic predisposition, and dysregulated immune responses, which leads to chronic inflammation and keratinocyte hyperproliferation. This review examines the treatment potential of important protein targets linked to psoriasis. Transcriptional regulators that affect inflammatory cascades and immune cell behavior include ACKR2, NFKBIZ, and TNIP1. Proteins like PK2 and KPNA2 affect the growth and differentiation of keratinocytes, and kynurenine pathway enzymes like KYNU and IDO lead to immunological imbalance. Inflammatory mediators like CXCL10 and CYR61, as well as antimicrobial peptides like LL37 and S100A15, are significantly increased in psoriatic lesions and maintain the chronic inflammatory state. Using information from the Protein Data Bank (PDB), the review also looks at the structural biology of these proteins, providing insights into molecular interactions and drug-binding sites. The study highlights the importance of these proteins in promoting individualised psoriasis treatment by combining molecular targeting techniques with new biologic treatments. This review surveys molecular proteins implicated in psoriasis, focusing on their potential as biomarkers or therapeutic targets. While many, such as CXCL10 or S100A15, are broadly involved in inflammatory cascades, others like LL37, TNIP1, and RORγt exhibit roles more uniquely tied to psoriatic pathology and may underpin future personalized treatment approaches.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115331"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of KLF4 regulation of autophagy in different physiological and pathological processes.","authors":"Chenglin Zhu, Qi Zhang, Hao Fan, Xinyu Zhang, Honggang Wang","doi":"10.1016/j.intimp.2025.115350","DOIUrl":"10.1016/j.intimp.2025.115350","url":null,"abstract":"<p><p>Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that exhibits both transcriptional activation and inhibition effects. It participates in the occurrence and development of various diseases by regulating processes such as cell cycle arrest, differentiation, and the maintenance of stem cell pluripotency. Autophagy, as a conserved lysosome dependent degradation pathway in eukaryotes, maintains cellular homeostasis by clearing abnormal proteins and damaged organelles. Its dysfunction is closely related to tumors, neurodegenerative diseases, metabolic disorders, and so on. Growing evidence indicates that KLF4 participates in multiple physiological and pathological processes through regulating autophagy, however, the underlying mechanisms are not fully understood. This article systematically reviewed the understanding of KLF4 and autophagy in recent years, critically synthesized the complex and context-dependent roles of KLF4-mediated autophagy regulation in different physiological and pathological processes, and analyzed the relevant molecular mechanisms, with an emphasis on identifying overarching regulatory patterns and functional consequences, hoping to provide theoretical basis for future in-depth research.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115350"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct STING-IRF3 activation determines IL-35⁺ Breg differentiation in rodent malaria.","authors":"Anni Feng, Qilong Li, Ning Jiang, Kunying Lv, Yixin Yang, Tong Liu, Ziwei Su, Yiwei Zhang, Xiaoyu Sang, Ying Feng, Ran Chen, Qijun Chen","doi":"10.1016/j.intimp.2025.115310","DOIUrl":"10.1016/j.intimp.2025.115310","url":null,"abstract":"<p><p>Augmented regulatory B cell (Breg) responses are commonly observed in malaria; however, the specific parasite components and Breg subtypes involved remain unclear. In this study, we investigated C57BL/6 mice infected with Plasmodium berghei ANKA, which induces cerebral malaria pathology, in comparison to P. yoelii YM, which does not. We found that distinct Breg types differentiated in response to these infections, driven by hemozoin-mediated Toll-like receptor 9 activation. Interleukin-35-positive (IL-35⁺) Breg expansion occurred in P. yoelii YM-infected mice but not in those infected with P. berghei ANKA. We demonstrated that stimulator of interferon genes (STING)-mediated interferon regulatory factor 3 (IRF3) phosphorylation suppressed IL-35⁺ Breg differentiation, potentially contributing to experimental cerebral malaria (ECM). In contrast, P. yoelii YM infection activated IRF3 in a STING-independent manner, promoting IL-35⁺ Breg expansion. These findings highlight IL-35⁺ Bregs as key modulators in malarial immunopathology.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115310"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic blockade of platelet-derived growth factor receptor-like protein attenuates cartilage degeneration and modulates cytokines in a spontaneous osteoarthritis mouse model.","authors":"Steve Wen-Neng Ueng, Yung-Heng Hsu, Yu-Chih Lin, Chih-Chien Hu, Yu-Tien Chiu, Yuhan Chang, Mei-Feng Chen","doi":"10.1016/j.intimp.2025.115294","DOIUrl":"10.1016/j.intimp.2025.115294","url":null,"abstract":"<p><strong>Objective: </strong>Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by the progressive breakdown of articular cartilage, affecting 10-15 % of older adults worldwide. There remains an urgent need for effective therapies to prevent chondrocyte loss, extracellular matrix (ECM) degradation, and OA progression.</p><p><strong>Methods: </strong>Through LC-MS/MS-based secretome analysis, we identified platelet-derived growth factor receptor-like protein (PDGFRL) as a novel factor significantly upregulated in osteoarthritic cartilage. To investigate its functional role, we utilized human cartilage plugs, STR/ort mice with spontaneous OA, and primary chondrocyte cultures to model ex vivo, in vivo, and in vitro conditions, respectively, allowing for comprehensive evaluation of PDGFRL's effects on chondrocytes and its underlying mechanisms.</p><p><strong>Results: </strong>PDGFRL expression was markedly elevated in both human and murine osteoarthritic cartilage. In the ex vivo human cartilage plug model, PDGFRL exerted deleterious effects by inducing chondrocyte clustering and reducing SOX9 expression. In vitro, PDGFRL treatment increased phosphorylation of Chk-2, p53, and eNOS, along with IGFBP3 secretion, indicating activation of apoptotic and ECM-degradative pathways. In STR/ort mice, anti-PDGFRL antibody treatment alleviated OA progression by reducing matrix-nonproducing chondrocytes, decreasing OARSI scores, suppressing aggrecan degradation and MMP-13 expression, and restoring SOX9 levels. Additionally, anti-PDGFRL treatment modulated systemic cytokine profiles by increasing chondroprotective IL-13 and IP-10, while elevating cartilage-destructive leptin and IL-7R. In contrast, exogenous PDGFRL protein administration did not exacerbate OA severity.</p><p><strong>Conclusion: </strong>Our findings identify PDGFRL as a therapeutic target, and suggest that inhibition using specific antibodies may offer a novel strategy to preserve cartilage integrity and slow disease progression.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115294"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin inhibits NF-κB p65/RelA-NLRP3 inflammasome-IL-1β axis, attenuates lipid droplet accumulation, and reprograms CD14/CD16 expression in monocytes exposed to colorectal tumor-conditioned medium.","authors":"Nihel Chahinez Djebri, Souad Zoudji, Aida Messaoud, Rabia Messali, Salim Loudjedi, Mourad Aribi","doi":"10.1016/j.intimp.2025.115299","DOIUrl":"10.1016/j.intimp.2025.115299","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) generates a complex tumor microenvironment (TME) known to profoundly alter the function and phenotype of immune cells, including monocytes. Key aspects of this environment can be mimicked by tumor-conditioned medium (TCM). Metformin has emerged as a promising candidate to counteract TCM-induced immune and inflammatory dysregulation. Therefore, this study aimed to evaluate the effects of metformin on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression, monocyte subset distribution, and lipid droplet (LD) accumulation upon exposure to colorectal TCM.</p><p><strong>Methods: </strong>Assays were performed on primary human monocytes exposed to colorectal TCM in the presence or absence of metformin.</p><p><strong>Results: </strong>TCM significantly increased nitric oxide (NO, p < 0.001) and hydrogen peroxide (H₂O₂, p < 0.001) production, intracellular free calcium ions (_ifCa²⁺) (p < 0.001) levels, expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB p65/RelA, p < 0.001), NLRP3 (p < 0.01), and interleukin-1 beta (IL-1β, p < 0.0001), as well as intracellular triacylglycerols (_iTAGs, p < 0.05), total cellular cholesterol content (_tccCHOL, p < 0.001), and lipid droplet accumulation (p < 0.05). It also impaired phagocytic activity (p < 0.05) and altered monocyte phenotype, along with a shift toward a CD14^low, CD16^high phenotype (p < 0.0001 for both markers). Notably, metformin treatment exerted broad and significant reversing effects, specifically on respiratory burst (NO, p < 0.05; H₂O₂, p < 0.01), _ifCa²⁺ levels (p < 0.01), NF-κB p65/RelA and NLRP3 expression, and IL-1β production (p < 0.0001 for all), and the lipid droplet accumulation (p < 0.0001), _iTAGs (p < 0.001), and _tccCHOL (p < 0.01). Metformin also significantly restored CD14 expression (p < 0.05) and increased CD14⁺ monocyte frequency (p < 0.01), while reducing CD16 expression (p < 0.05) and CD16⁺ monocyte frequency (p < 0.01). However, it had no significant effect on phagocytosis in TCM-exposed monocytes (p > 0.05).</p><p><strong>Conclusions: </strong>Our findings highlight metformin's selective immunometabolic reprogramming capacity in monocytes exposed to colorectal tumor-derived signals, supporting its potential as a context-specific immunomodulator. This study lays the groundwork for future translational research on metformin as an adjunctive agent in inflammation-driven tumor settings.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115299"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into SUMOylation and its role in cancer pathogenesis: bridging oncogenesis, immunity, and therapeutic opportunities.","authors":"Wei Qu, Jinning Gu, Shanshan Liu, Wen Xiao, Yanwei Li","doi":"10.1016/j.intimp.2025.115332","DOIUrl":"10.1016/j.intimp.2025.115332","url":null,"abstract":"<p><p>SUMOylation is a post-translational modification mediated by SUMO proteins, a family of small ubiquitin-like biological macromolecules that covalently attach to specific lysine residues in target proteins. This modification regulates various macromolecular functions, including transcriptional control, subcellular localization, DNA repair, and cell cycle progression. Recent advances have unveiled the multifaceted roles of SUMOylation in cancer pathogenesis, encompassing oncogenesis, immune modulation, and therapeutic resistance. This review details the molecular mechanisms of SUMOylation and its deregulation in tumor development, highlighting its role in genomic stability, transcriptional regulation, and signal transduction, key elements in tumor progression and metastasis. Additionally, the role of SUMOylation in the tumor microenvironment (TME) and immune evasion is explored, with emphasis on its interactions with immune checkpoint pathways and inflammatory signaling. Insights into SUMOylation's involvement in treatment resistance, particularly chemoresistance and radioresistance, are presented alongside an overview of emerging therapeutic strategies targeting this pathway. The potential of SUMOylation as a diagnostic and prognostic biomarker is also discussed, underscoring its translational significance in personalized oncology. By bridging oncogenesis, immune regulation, and therapy, this review aims to unify the current understanding of SUMOylation's role in cancer. Targeting SUMOylation presents a promising avenue for developing innovative cancer therapies that address immune modulation and treatment resistance. This review provides a roadmap for future research, fostering advancements in SUMOylation biology and its therapeutic applications in oncology.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115332"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DB75 targets PRMT1 to suppress liver metastasis and synergizes with PD-L1 blockade for enhanced therapeutic efficacy.","authors":"Sumin Sun, Haili Hu, Peihua Sun, Yuan Gao, Yu Huang, Xue Gong, Liming Chen","doi":"10.1016/j.intimp.2025.115327","DOIUrl":"10.1016/j.intimp.2025.115327","url":null,"abstract":"<p><p>Liver metastasis represents a major clinical challenge, primarily attributed to its unfavorable prognosis and scarce therapeutic alternatives. This study investigated protein arginine methyltransferase 1 (PRMT1) and its highly selective inhibitor furamidine (DB75), exploring their roles in liver metastasis and their potential for combination therapy with anti-programmed death-ligand 1 monoclonal antibody (anti-PD-L1 mAb). PRMT1 regulates malignant phenotypes of tumour cells through asymmetric dimethylation of arginine residues in various cancers. Using multiple liver metastasis models, including breast cancer liver metastasis (BCLM), we demonstrated that PRMT1 expression was upregulated in liver metastases and highly metastatic cells, while DB75 effectively suppressed tumour proliferation, clonogenicity, and hepatic colonization. RNA sequencing analysis revealed significant upregulation of Tmem196 within the tumour microenvironment following DB75 treatment. Functionally, Tmem196 exhibited tumour-suppressive effects in cancer cells but paradoxically promoted α-smooth muscle actin expression in cancer-associated fibroblasts (CAFs), driving a pro-tumorigenic phenotype through TMEM196. Notably, DB75 selectively upregulated TMEM196 in CAFs but not in tumour cells. Given previous reports linking activated CAFs to elevated PD-L1 expression and immunosuppression, we combined DB75 with anti-PD-L1 mAb and observed synergistic inhibition of metastatic progression, which was significantly superior to anti-PD-L1 mAb monotherapy. This study elucidates the mechanism by which DB75 suppresses BCLM and provides preclinical evidence for PD-L1 blockade-based combinatorial immunotherapy.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115327"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing the chimeric antigen receptor engineered cells in gastrointestinal cancer immunotherapy.","authors":"Arash Dadvand, Mohsen Nooroulahi, Somaieh Matin, Elnaz Faghfuri","doi":"10.1016/j.intimp.2025.115321","DOIUrl":"10.1016/j.intimp.2025.115321","url":null,"abstract":"<p><p>Gastrointestinal (GI) cancers pose a significant global health concern. Their prevalence is continually increasing, and managing them remains a significant clinical hurdle. Adoptive cell therapies designed to express chimeric antigen receptors (CARs) or transgenic T cell receptors (TCRs) to identify and destroy cancer cells have emerged as a promising strategy for achieving long-term remissions in cancer patients. To be effective, the engineered cells must persist at therapeutically sufficient levels while minimizing off-tumor toxicities, which has proven difficult to realize outside of hematologic malignancies. This review comprehensively discusses the progress and use of CAR-immune cells in treating GI cancers. We looked into different sources of these cells, CAR design strategies, and the latest advancements in CAR-cell therapy for GI cancers, while providing organ-specific preclinical and clinical insights across colorectal, gastric, hepatic, and pancreatic malignancies. Moreover, we discussed the current challenges and suggested potential methods to improve the efficacy and safety of CAR-cell therapy. This review emphasizes the unique potential of CAR-NK cells as low-toxicity, \"off-the-shelf\" alternatives to CAR-T cells. It details innovative strategies to overcome solid tumor challenges-including metabolic reprogramming, dual-targeting approaches, and microenvironment modulation. It is concluded that CAR cells have significant potential to revolutionize the treatment of gastrointestinal cancer, paving the way for rational combinations that open up new therapeutic perspectives.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"164 ","pages":"115321"},"PeriodicalIF":4.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}