Frontiers in Immunology最新文献

{"title":"Orchestration of the tumor microenvironment by citrus flavonoids: from preclinical mechanisms to translational therapeutic.","authors":"Siyao Ma, Xuebing Wang, Mingzhu Li, Wenping Wang, Yanyi Ren, Yue Shen, Ke Yang, Ze Zhang, Zitong Feng, Shuhan Tang","doi":"10.3389/fimmu.2026.1806088","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1806088","url":null,"abstract":"<p><p>Malignant lung tumors are the leading cause of cancer-related mortality worldwide, and therefore remodeling of the tumor microenvironment (TME) has become an important strategy to overcome anti-tumor therapy resistance in lung cancer. Flavonoid components isolated from Citri Reticulatae Pericarpium (CRP), such as nobiletin, hesperidin, and tangeretin, have been shown to modulate the lung cancer TME in a highly relevant manner. The present narrative review collected literature from the PubMed, Web of Science, Embase, CNKI, and Wanfang databases between 2016 and 2026, and hence discussed the molecular mechanisms by which CRP flavonoids reshape the lung cancer TME, namely their regulation of oxidative stress-inflammation homeostasis, correction of lipid metabolic reprogramming, induction of pyroptosis, and inhibition of epithelial-mesenchymal transition. Discussion of the role of EMT and tumor angiogenesis suppression were also presented. Then evidence regarding the modulation of emerging targets was introduced, namely ferroptosis and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which are both promising targets in lung cancer models. Translational prospects of CRP flavonoids were led to enhancing immune checkpoint inhibitor (ICI) efficacy and developing nano-delivery systems. The article first outlined the fundamental barriers, then gave a very systematic and critical review of the contradictory findings, context-dependent effects, and methodological limitations in the existing literature; and then pointed out the gaps in frontier research. Therefore, it provides an excellent theoretical foundation for the research and development of anti-lung cancer drugs from CRP flavonoids, while also objectively identifying the current knowledge gaps and clinical translation bottlenecks.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1806088"},"PeriodicalIF":5.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoparticles that modulate immune cells - an important strategy for the future treatment of tumors.","authors":"Yan Zhao, Guoxing Zhang, Xin Nie, Jingyuan Ren, Dequan Xu, Hongbo Yan, Jianxin Zhao, Laga Tong, Lei Zhao, Haifeng Liu","doi":"10.3389/fimmu.2026.1803646","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1803646","url":null,"abstract":"<p><p>Cancer has become a major public health issue that seriously threatens human health. With the widespread development and application of drug-loaded nanosystems in tumor therapy, numerous studies have confirmed that various nanoparticles can exert anti-tumor activity by regulating one or more immune cells in the tumor microenvironment (TME), including depleting M2-type TAMs in the TME, limiting the recruitment and localization of TAMs, reprogramming M2-type TAMs into M1-type TAMs, enhancing NK cells homing or function, promoting DCs maturation, inhibiting TANs recruitment or altering their polarity, reducing circulating and tumor-infiltrating MDSCs, altering MDSCs phenotype or inhibiting MDSCs functions (including nanocapsules, metal-organic frameworks, micelles, polymers, dendritic macromolecules, liposomes, and other material nanoparticles), promoting CD8⁺ T cells proliferation or activity and reducing the number of Tregs (including nanoparticles composed of liposomes, gels, cerium, and selenium, hyaluronic acid-modified nanoparticles, nanocapsules, nanovesicles, other material nanoparticles, and nanoparticles combined with other treatment modalities), besides, some nanoparticles can exert anti-tumor activity by regulating two or more types of immune cells in the TME. In short, nanoparticles targeting immune cells will become an important strategy in tumor treatment based on the advantages of nanoparticles in enhancing efficacy and reducing toxicity in tumor therapy, as well as the important role of immune cells in tumor occurrence and development. In this article, we will provide a detailed introduction to nanoparticles that exert anti-tumor activity by regulating immune cells in the TME and briefly introduce the mechanisms by which nanoparticles regulate immune cells.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1803646"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TACE plus lenvatinib and envafolimab for conversion therapy in unresectable HCC: a prospective pilot study.","authors":"Yuhao Su, Yuxin Liang, Deyuan Zhong, Yahui Chen, Ming Wang, Qinyan Yang, Hongtao Yan, Xiaolun Huang","doi":"10.3389/fimmu.2026.1802197","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1802197","url":null,"abstract":"<p><strong>Background: </strong>Most patients with hepatocellular carcinoma (HCC) are diagnosed at intermediate or advanced stages, when curative resection is not feasible. Conversion therapy aiming to downstage tumors and enable surgical resection has emerged as a potential strategy. We performed an exploratory, single-arm pilot study to assess the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and the envafolimab in this setting.</p><p><strong>Methods: </strong>This single-center, open-label, single-arm pilot trial enrolled patients with Barcelona Clinic Liver Cancer stage B or C unresectable HCC between April and September 2024. Patients received conventional TACE combined with oral lenvatinib and subcutaneous envafolimab until surgical conversion, disease progression, unacceptable toxicity, or death. The primary endpoint was the conversion rate to curative-intent resection. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), pathological response, progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>Fifteen patients were enrolled. According to mRECIST criteria, the ORR was 53.3% and the DCR was 86.7%. Nine patients (60.0%) achieved sufficient tumor downstaging to undergo curative-intent surgery, and all achieved R0 resection. Pathological complete or major response was observed in five resected patients (55.6%). After a median follow-up of 16 months, the estimated median PFS was 12.0 months. One patient died during follow-up, yielding a 1-year OS of 100% and an 18-month OS of 93.3%. Treatment-emergent adverse events were consistent with the known profiles of TACE, lenvatinib, and envafolimab; however, gastrointestinal bleeding was observed and represents an important safety concern that warrants careful risk stratification and proactive management.</p><p><strong>Conclusion: </strong>In this small pilot study, TACE combined with lenvatinib and envafolimab was associated with encouraging antitumor activity and a relatively high conversion-to-resection rate, with an acceptable safety profile. However, the limited sample size and single-arm design preclude definitive causal conclusions, and gastrointestinal bleeding emerged as an important risk. These preliminary findings suggest the need for validation in larger, controlled trials.</p><p><strong>Clinical trial registration: </strong>https://www.chictr.org.cn/showproj.html?proj=222901, identifier ChiCTR2400081945.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1802197"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-32 as a potential biomarker and therapeutic target in cardiovascular disease.","authors":"Lingyue Qiu, Jing Ye, Ling Liu, Qingwei Ji","doi":"10.3389/fimmu.2026.1755759","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1755759","url":null,"abstract":"<p><p>Cardiovascular diseases remain a leading cause of death worldwide, driven by complex pathological mechanisms involving various cytokines and inflammatory responses. IL-32, a recently discovered cytokine, has emerged as a key player in the pathogenesis of cardiovascular diseases, including atherosclerosis, myocardial infarction, and heart failure. This review summarizes the biological characteristics of IL-32 and its role in cardiovascular diseases, explores its involvement in inflammatory responses and other pathological processes, and evaluates its potential as both a biomarker and a therapeutic target. Collectively, this review aims to provide new insights for the prevention and treatment of cardiovascular diseases.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1755759"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors.","authors":"Phuc Q Pham, Quaovi H Sodji","doi":"10.3389/fimmu.2026.1822583","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1822583","url":null,"abstract":"<p><p>Monospecific Chimeric Antigen Receptor (CAR) T cell therapy against hematological malignancies targeting specific tumor-associated antigen (TAA) has gained clinical success in recent years. Despite their clinical outcomes, challenges including antigen escape, time and labor-intensive manufacturing process, and diminished efficacy especially against solid tumors persist. While allogeneic monospecific \"off-the-shelf\" CAR T cell therapy from healthy donors with knockout of alloreactive genes using gene editing tools such as CRISPR/Cas9 or TALEN has been evaluated to overcome manufacturing challenges, these allogeneic CAR T cells still face antigen escape. As such, adapter-based CAR T cells that can be redirected by small-molecule adapters to target multiple TAAs have emerged as an alternative therapeutic platform to overcome antigen escape. However, autologous adapter-based CAR T cell manufacturing remains time and labor intensive and scales poorly. Furthermore, chemotherapy-induced T cell dysfunction may compromise both manufacturing and efficacy of autologous CAR T cells. In this comprehensive review, we highlight advantages and limitations of the adapter-based CAR T platform and discuss how allogeneic manufacturing can be applied to adapter-based CAR T as a potential \"off-the-shelf\" therapeutic for treating multiple cancer types and overcome antigen escape.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1822583"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATG5-mediated inducible autophagy sustains CAR-T cell durability under solid tumor stress.","authors":"Sang-Eun Jung, Minji Lim, Hyungwoo Jeong, Youngchae Moon, Hyungseok Seo","doi":"10.3389/fimmu.2026.1720544","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1720544","url":null,"abstract":"<p><p>Autophagy functions as a context-dependent stress adaptation pathway in T cells; however, its role in sustaining chimeric antigen receptor (CAR)-T cell function within solid tumor environments remains insufficiently defined. In this study, we investigated whether ATG5-mediated autophagy regulation contributes to CAR-T cell functional durability under tumor-associated stress conditions. ATG5 overexpression (OE) CAR-T cells did not increase basal autophagy activity but instead selectively enhanced autophagy flux in response to inducible stimuli. Under tumor-mimicking immunosuppressive conditions, ATG5 OE CAR-T cells maintained cytotoxic activity during prolonged antigen exposure and exhibited preserved effector cytokine production together with reduced oxidative stress. Consistent with these <i>in vitro</i> findings, ATG5 OE CAR-T cells exhibited enhanced antitumor efficacy <i>in vivo</i> under IR-preconditioned settings, characterized by improved tumor control and survival, which was associated with sustained effector function of tumor-infiltrating CAR-T cells. Collectively, these findings demonstrate that reinforcing inducible autophagy capacity through ATG5 promotes the maintenance of CAR-T cell function under tumor-associated challenges, highlighting a targeted strategy to enhance CAR-T cell persistence in solid tumor immunotherapy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1720544"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis and functional validation reveal the oncogenic role of TRIP13.","authors":"Yuanqiao Zhao, Yongqi Zhao, Ruilin Liu, Jing Li, Yinhuai Wang","doi":"10.3389/fimmu.2026.1691436","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1691436","url":null,"abstract":"<p><strong>Background: </strong>Thyroid hormone receptor-interacting protein 13 (TRIP13), an enzyme from the AAA-ATPase family, facilitates the assembly or disassembly of protein complexes and participates in various biological processes. However, its impact on cancer immune infiltration and pan-cancer prognosis remains largely unexplored.</p><p><strong>Methods: </strong>Pan-cancer multi-omics data from publicly available resources were systematically analyzed to evaluate TRIP13 expression across various cancer types and its association with patient prognosis. In addition, functional enrichment analyses were conducted to investigate TRIP13-related biological processes and pathways. The analysis included GSEA enrichment, correlation with immune regulator expression, tumor immune cell infiltration, association with tumor mutational burden (TMB), and correlation with microsatellite instability (MSI). Additionally, single-cell data were used to explore the expression and potential role of TRIP13 at the single-cell level. We subsequently conducted a series of <i>in vitro</i> experiments.</p><p><strong>Results: </strong>Our comprehensive pan-cancer analysis reveals significantly elevated TRIP13 expression across multiple cancer types and links it to poor prognostic outcomes. TRIP13 primarily activates pathways such as ubiquitination, cell cycle regulation, and DNA repair to drive tumor progression. Additionally, TRIP13 expression exhibits complex associations with various immune regulators and immune cells. In prostate cancer, TRIP13 shows marked overexpression and is associated with unfavorable prognosis. We identified a significant upregulation of TRIP13 in proliferative tumor stem-like populations in prostate cancer. Consistently, prostate cancer cells that acquired resistance to CDK4/6 inhibitors displayed marked TRIP13 overexpression, and functional assays revealed that TRIP13 modulates cellular sensitivity to these agents. Mechanistically, we demonstrated that E2F1 transcriptionally activates TRIP13, which in turn drives the upregulation of the downstream ubiquitin ligase HECTD3.</p><p><strong>Conclusion: </strong>This study reveals aberrant TRIP13 expression across multiple cancers and its association with immune modulation and tumor aggressiveness. The elevation of TRIP13 in palbociclib resistant prostate cancer, together with the regulatory E2F1-TRIP13-HECTD3 axis, highlights its potential as a prognostic biomarker and therapeutic target.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1691436"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial biology and immune crosstalk in breast cancer: therapeutic opportunities and challenges.","authors":"Yulin Zeng, Yingjie Guo","doi":"10.3389/fimmu.2026.1715998","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1715998","url":null,"abstract":"<p><p>Mitochondria are central regulators of breast cancer progression and therapy response, acting beyond energy metabolism to integrate redox balance, regulated cell death, metabolic plasticity, and immune signaling. This review summarizes how mitochondrial metabolism, dynamics, stress signaling, and quality-control pathways shape tumor heterogeneity, immune evasion, and treatment outcomes across tumor, immune, and stromal compartments. In breast cancer, subtype-specific mitochondrial programs influence oxidative phosphorylation, fatty acid oxidation, glutaminolysis, lactate accumulation, and mtDAMP signaling, thereby contributing to immune suppression and therapeutic resistance. We further discuss how mitochondrial regulation of apoptosis, ferroptosis, cuproptosis, and pyroptosis reveals both therapeutic opportunities and unresolved limitations. Although mitochondria-targeted strategies show translational promise, their clinical application remains constrained by metabolic heterogeneity, adaptive rewiring, immune-cell liability, and insufficient biomarkers. Overall, mitochondria represent a context-dependent therapeutic axis in breast cancer.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1715998"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptome and single-cell RNA sequencing identifies small GTPase-associated biomarkers in ulcerative colitis.","authors":"Meilin Chen, Weiguo Dong","doi":"10.3389/fimmu.2026.1782885","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1782885","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is a chronic, multifactorial inflammatory bowel disease. The involvement of small GTPase-related genes (SGRGs) in UC remains poorly defined. This study aims to identify SGRGs associated with UC and elucidate the molecular mechanisms by which they regulate the pathological progression of UC.</p><p><strong>Methods: </strong>Multiple transcriptomic datasets were integrated to identify candidate SGRGs in UC. Four machine learning algorithms were utilized for biomarker screening, followed by the construction of a diagnostic nomogram. The robustness of the identified biomarkers and the nomogram was rigorously evaluated through external validation in multiple independent cohorts. Furthermore, the associations between biomarkers and clinical severity, as well as their capacity for differential diagnosis (UC vs. Crohn's disease (CD)), were assessed. Functional enrichment, immune infiltration, and cross-dataset single-cell RNA sequencing (scRNA-seq) were employed for in-depth mechanistic investigation. <i>In vivo</i> experiments validated core gene expression.</p><p><strong>Results: </strong>Three biomarkers (<i>ARHGEF3</i>, <i>S100A8</i>, and <i>RHOU</i>) were successfully identified and validated across multiple independent cohorts. The nomogram constructed based on these biomarkers exhibited excellent diagnostic performance (AUC = 0.991 in the training set, 0.938 and 0.968 in the external validation cohort). Notably, the expression levels of these biomarkers significantly correlated with clinical severity and pathological mucosal states, demonstrating their capacity to reflect disease activity and monitor progression. Furthermore, among the identified biomarkers, <i>ARHGEF3</i> significantly differentiated UC from CD (p < 0.05), while all three markers exhibited discriminative potential with AUC values exceeding 0.6. Functional annotation illustrated that they were commonly enriched within pathways encompassing \"Tight junction\" and \"Leukocyte transendothelial migration\". Immune infiltration assessment demonstrated 27 differentially expressed immune cells (DEICs) among the UC and control groups. Cross-dataset scRNA-seq analysis further confirmed that macrophages were the key cells, exhibiting significant metabolic reprogramming and functional heterogeneity in UC. <i>In vivo</i> experiments confirmed the expression of above biomarkers in UC.</p><p><strong>Conclusion: </strong>This study systematically identifies <i>ARHGEF3</i>, <i>S100A8</i>, and <i>RHOU</i> as novel UC diagnostic biomarkers, implicating them in disease progression via immune regulation and macrophage function. These findings provide a new basis for precise diagnosis and targeted therapy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1782885"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From immune exclusion to exhaustion: tumor microenvironment drives therapy response.","authors":"Nemanja Maletin","doi":"10.3389/fimmu.2026.1785587","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1785587","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of cancer progression and therapeutic resistance. Far from being a passive scaffold, the TME comprises diverse immune and stromal components, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, dysfunctional vasculature, and metabolic stressors, that collectively shape tumor evolution and modulate treatment response. In this review, we explore how spatial immune exclusion, immune cell dysfunction, hypoxia, and metabolic reprogramming create barriers to effective therapy, particularly in tumors refractory to immune checkpoint inhibition. We detail the molecular and cellular mechanisms by which the TME enforces immune suppression and dampens the efficacy of chemotherapy, radiotherapy, and immunotherapy. Moreover, we highlight emerging strategies to therapeutically reprogram the TME, including anti-fibrotic therapies, vascular normalization, myeloid reprogramming, metabolic modulation, and novel platforms such as oncolytic viruses, nanoparticles, and bispecific antibodies. By dissecting both established and innovative approaches, we emphasize the importance of combinatorial and context-specific interventions aimed at increasing immune accessibility and functional competence in selected contexts, thereby improving the likelihood of therapy responsiveness. A deeper understanding of the TME's complexity offers critical opportunities to overcome resistance and improve outcomes across cancer types.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1785587"},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}