Journal for Immunotherapy of Cancer最新文献

{"title":"m⁶A-driven transcriptomic rewiring in tumor immune surveillance.","authors":"Parmanand Malvi, Patrick Ball, Romi Gupta, Narendra Wajapeyee","doi":"10.1136/jitc-2025-012744","DOIUrl":"10.1136/jitc-2025-012744","url":null,"abstract":"<p><p>RNA molecules are subject to extensive post-transcriptional modifications that fine-tune their stability, localization, and function. Among the more than 100 known RNA modifications, N6-methyladenosine (m⁶A) is the most abundant internal mark on eukaryotic messenger RNAs. This dynamic modification is installed by methyltransferases (\"writers\"), removed by demethylases (\"erasers\"), and interpreted by RNA-binding proteins (\"readers\") to modulate gene expression. In this review, we examine the mechanisms governing m⁶A deposition and its broad impact on mRNA fate. We then focus on the emerging roles of m⁶A in shaping antitumor immune responses and discuss how targeting m⁶A-regulated pathways can enhance the efficacy of existing immunotherapies. Finally, we highlight recent advances and ongoing challenges in the development of drugs that target key regulators of m⁶A RNA modifications.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory polymorphisms of <i>MSH6</i>, <i>MSH2</i>, <i>FBXO11,</i> and <i>PPP1R21</i> genes affect survival of patients with immunotherapy-treated lung cancer.","authors":"Martina Esposito, Sara Noci, Francesca Minnai, Tania Camboni, Eleonora Mangano, Manuela Gariboldi, Elisa Frullanti, Claudia Bareggi, Elena Collovà, Serena Girelli, Sheila Piva, Gabriella Farina, Arianna Pagliaro, Luca Toschi, Luca Sala, Diego Luigi Cortinovis, Francesca Colombo","doi":"10.1136/jitc-2025-011526","DOIUrl":"10.1136/jitc-2025-011526","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICI) improved survival of patients with non-small cell lung cancer (NSCLC), yet many patients do not respond to treatment. The identification of markers for ICI response remains an unmet clinical need. This study hypothesizes that host genetics influences the response to ICI, contributing to the variability in efficacy among individuals.</p><p><strong>Methods: </strong>We conducted a genome-wide association study (GWAS) in patients with NSCLC on ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab, to identify germline variants associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) at 24 months after the start of ICI therapy. Genomic DNA was genotyped using Axiom Precision Medicine Research Arrays. Raw data were processed with Axiom Analysis Suite, and quality checked with PLINK software. Imputation to the whole genome was done on the Michigan Imputation Server. Association analyses were performed for ORR (logistic regression with PLINK2 software) and survival (Cox proportional hazards model, with GenAbel package in R environment), with appropriate covariates. Variants were annotated for functional significance using SNPnexus and FUMA. Post-GWAS analyses, including colocalization, were performed to explore the function of the identified variants. Their possible role as expression quantitative trait loci was investigated in different databases (GTEx, eQTLGen, TCGA).</p><p><strong>Results: </strong>No genome-wide significant associations were found for ORR or PFS, while a locus on chromosome 2 (lead variant: rs111648355) showed near genome-wide significance (p value=6.3×10⁻⁸) for OS. Patients with minor alleles of these variants exhibited significantly worse OS (HR=5.1, 95% CI: 2.9 to 9.2). Functional annotation linked these variants to regulatory effects on genes including <i>MSH2</i>, <i>MSH6</i>, <i>PPP1R21</i>, <i>FBXO11</i>, and <i>STON1</i>. These genes play a role in mismatch repair, endosomal trafficking, or major histocompatibility complex class II regulation, and might influence the response to immunotherapy.</p><p><strong>Conclusions: </strong>This study identifies an association between a genomic locus on chromosome 2 and OS in patients with NSCLC treated with ICI. Although these results need validation in larger cohorts and functional studies to elucidate the underlying mechanisms, they highlight the potential of germline variants as predictive biomarkers of response to ICI.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanofilament immunotherapy induces potent antitumor vaccine responses.","authors":"Kevin Neil, Samuel Génier, Marie-Ève Poisson, Julie Douchin, Hugo Giguère, Lauren Daniel, Melisa Farias Gonzalez, Sally Huang, Vincent Quoc-Huy Trinh, Lee-Hwa Tai, Sébastien Rodrigue, Jean-François Millau","doi":"10.1136/jitc-2024-011331","DOIUrl":"https://doi.org/10.1136/jitc-2024-011331","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint inhibitors revolutionized cancer treatment by potentiating antitumor immune responses. However, many patients do not respond to these therapies, often due to the lack of a pre-existing immune response against cancer cells. Developing immunotherapies that promote cancer-cell antigen recognition, and the initiation of antitumor immune responses could thus improve response rates.</p><p><strong>Methods: </strong>We established multimodal nanofilament immunotherapy as an antigen-agnostic in situ cancer vaccine modality. Through genetic engineering of the M13 bacteriophage, nanofilaments displaying combinations of therapeutic agents were generated to guide immune recognition and response against cancer cells. TAT003 is a multimodal nanofilament combining the natural adjuvant properties of M13 with the display of both anti-PD-L1 single-chain antibody fragments (scFvs) and interleukin-2 (IL-2) molecules. It was developed to bind to the surface of cancer cells and transform them into immunological targets. After validation of TAT003's biological activities in vitro and assessment of its biodistribution, its potency was evaluated after intratumoral administration in murine syngeneic tumor models, both as a single agent and in combination with Programmed Death protein 1 (PD-1) blockade therapy. In addition, the mechanism of action of TAT003 was characterized using cytokine and immune profiling and T-cell activation assays.</p><p><strong>Results: </strong>TAT003 nanofilaments displayed several copies of biologically active anti-Programmed Death ligand 1 (PD-L1) and IL-2 molecules. On intratumoral injection, TAT003 attached durably to the tumor, thus limiting systemic exposure to the drug. TAT003 profoundly remodeled the tumor microenvironment of injected lesions, where it initiated a robust myeloid-cell infiltrate, and promoted the invasion of non-injected, contralateral lesions by T cells. This translated into potent regression of both injected and non-injected tumors in several cancer models, and potentiated PD-1 blockade therapy. TAT003 treatment induced the expansion of cancer-cell specific effector T cells systemically, providing a long-lasting antitumor vaccine response.</p><p><strong>Conclusions: </strong>Multimodal nanofilament immunotherapy is a novel approach to mounting systemic antitumor immune responses in situ by physically attaching large immunostimulatory molecules to cancer cells. TAT003 induced marked tumor regression by leveraging synergies between therapeutic agents displayed on its surface while offering a favorable tolerability profile. The results presented here establish multimodal nanofilaments as an innovative and versatile immunotherapy platform for developing in situ cancer vaccines.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPV-positive HNSCC and Fc-silent PD-1 blockade: a clinical discrepancy that raises next immunological questions.","authors":"Kohei Okuyama, Junya Fujimoto, Souichi Yanamoto","doi":"10.1136/jitc-2025-012728","DOIUrl":"10.1136/jitc-2025-012728","url":null,"abstract":"<p><p>The recent phase 3 trial of the Fc-silent anti-programmed cell death protein-1 (PD-1) antibody finotonlimab demonstrated promising clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, an unexpected finding emerged: human papillomavirus (HPV)-positive patients-typically responsive to PD-1 blockade-did not appear to benefit, with a subgroup HR favoring the control arm. This clinical discrepancy raises important mechanistic questions. We hypothesize that the abrogation of Fcγ receptor (FcγR)-mediated functions, while designed to preserve PD-1⁺ T cells, may inadvertently attenuate innate immune mechanisms that are especially relevant in virally driven tumors. In immune-inflamed HPV-positive HNSCC, antitumor activity may depend not only on T-cell activation but also on FcγR-dependent myeloid and natural killer cell function. These considerations prompt further evaluation of how Fc engineering may interact with tumor immune contexture, particularly in virally associated cancers. We suggest experimental validation and stratified analysis in future studies to clarify these context-specific effects.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA Ligand Atlas DIA: extending the benign immunopeptidomics resource with increased sensitivity through data-independent acquisition mass spectrometry.","authors":"Leon Bichmann, Ana Marcu, Daniel Johannes Kowalewski, Lena Katharina Freudenmann, Linus Backert, Lena Mühlenbruch, Maren Lübke, Philipp Wagner, Tobias Engler, Sabine Matovina, Mathias Hauri-Hohl, Roland Martin, Holger Moch, Luca Regli, Michael Weller, Markus W Löffler, Juliane S Walz, Oliver Kohlbacher, Hannes Röst, Hans-Georg Rammensee, Marian C Neidert","doi":"10.1136/jitc-2025-012083","DOIUrl":"10.1136/jitc-2025-012083","url":null,"abstract":"<p><p>The human leukocyte antigen (HLA)-presented peptide repertoire, termed immunopeptidome, plays a crucial role for T-cell mediated immune reactions. Previously, the human immunopeptidome of non-malignant tissues has been mapped in a large-scale study, the HLA Ligand Atlas, via high-resolution data-dependent acquisition (DDA) mass spectrometry. This publicly available and user-friendly web interface (https://hla-ligand-atlas.org) is frequently used as a benign tissue reference in antigen discovery, especially for immunotherapy of cancer. Here, we extend the HLA Ligand Atlas resource with paired data-independent acquisition (DIA) runs for all tissue-subject combinations. This novel dataset comprises 946 DIA HLA class I and II immunopeptidomic runs from 242 non-malignant human samples across 18 subjects and 29 distinct tissues. Together with the published DDA runs, this extends the range and depth of analyses performed on the HLA Ligand Atlas dataset. In a concise analysis, we showcase advantages of DIA over DDA concerning spectral sampling and sensitivity. These findings are attributed to the increased dynamic range in DIA, enabling the identification of peptide transitions with low signal intensities. Moreover, we demonstrate the superior sensitivity by applying an HLA-A*02:01 allotype-specific spectral library search to identify and quantify HLA-presented peptides. We encourage reanalysis of the provided DDA and DIA data in combination as a reference for future research concerning human immunology.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How can we increase the value of clinical trials with immunotherapy?","authors":"Michael B Atkins, David F Mcdermott","doi":"10.1136/jitc-2025-012456","DOIUrl":"10.1136/jitc-2025-012456","url":null,"abstract":"<p><p>In the 40 years since the initial studies with interleukin-2 led to the Society for Immunotherapy of Cancer's creation, immunotherapy has become a crucial pillar of cancer therapy that is extending and improving countless lives worldwide. Checkpoint inhibitor immunotherapy has become a standard of care treatment for over 20 distinct types of cancer, and other immunotherapy approaches such as novel engineered cytokines, T-cell engagers, oncolytic viruses, personalized cancer vaccines and various cellular therapies are in active development and have already or may eventually receive regulatory approval. This commentary examines what we have learned during this remarkable four-decade drug development journey and how we can best leverage that knowledge to efficiently develop, license and apply future immunotherapy approaches.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial TCR clonality and clonal expansion in the in situ microenvironment of non-small cell lung cancer.","authors":"Hui Yu, Anastasia Magoulopoulou, Rose-Marie Amini, Maria Paraskevi Chatzinikolaou, Masafumi Horie, Amanda Lindberg, Artur Mezheyeuski, Max Backman, Andreas Metousis, Hans Brunnström, Millaray Marincevic, Johan Botling, Johanna Sofia Margareta Mattsson, Klas Kärre, Karin Leandersson, Mats Nilsson, Carina Strell, Patrick Micke","doi":"10.1136/jitc-2025-012089","DOIUrl":"10.1136/jitc-2025-012089","url":null,"abstract":"<p><strong>Background: </strong>T-cell activation and clonal expansion are essential to effective immunotherapy responses in non-small cell lung cancer (NSCLC). The distribution of T-cell clones may offer insights into immunogenic mechanisms and imply potential prognostic and predictive information.</p><p><strong>Methods: </strong>We analyzed α/β T-cell receptor (TCR) clonality using RNA-sequencing of bulk frozen tumor tissue from 182 patients with NSCLC. The data was integrated with molecular and clinical characteristics, extensive in situ imaging, and spatial sequencing of the tumor immune microenvironment. TCR clonality was also determined in an independent cohort of nine patients with immune checkpoint-treated NSCLC.</p><p><strong>Results: </strong>TCR clonality (Gini index) patterns ranged from high T-cell clone diversity with high evenness (low Gini index) to clonal dominance with low evenness (high Gini index). Generally, TCR clonality in cancer was lower than in matched normal lung parenchyma distant from the tumor (p=0.021). The TCR clonality distribution between adenocarcinoma and squamous cell carcinoma was similar; however, smokers showed a higher Gini index. While in the operated patient with NSCLC cohort, TCR clonality was not prognostic, in an immune checkpoint inhibitor-treated cohort, high TCR clonality was associated with better therapy response (p=0.016) and prolonged survival (p=0.003, median survival 13.8 vs 2.9 months). On the genomic level, a higher Gini index correlated strongly with a lower frequency of epidermal growth factor receptor (EGFR) and adenomatous polypsis coli (APC) gene mutations, but a higher frequency of P53 mutations, and a higher tumor mutation burden. In-depth characterization of the tumor tissue revealed that high TCR clonality was associated with an activated, inflamed tumor phenotype (PRF1, GZMA, GZMB, INFG) with exhaustion signatures (LAG3, TIGIT, IDO1, PD-1, PD-L1). Correspondingly, PD-1+, CD3+, CD8A+, CD163+, and CD138+immune cells infiltrated cancer tissue with high TCR clonality. In situ sequencing recovered single dominant T-cell clones within the patient tumor tissue, which were predominantly of the CD8 subtype and localized closer to tumor cells.</p><p><strong>Conclusion: </strong>Our robust analysis pipeline characterized diverse TCR repertoires linked to distinct genotypes and immunologic tumor phenotypes. The spatial clustering of expanded T-cell clones and their association with immunological activation underscores a functional, clinically relevant immune response, particularly in patients with NSCLC treated with checkpoint inhibitors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-faced CXCL5 holds the key to unlocking immunotherapy in obese pancreatic cancer.","authors":"Liping Liang, Yongjian Zhou, Le Liu","doi":"10.1136/jitc-2025-012566","DOIUrl":"10.1136/jitc-2025-012566","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by a profoundly immunosuppressive tumor microenvironment and resistance to immunotherapy. Obesity, a modifiable risk factor that increases PDAC incidence, exacerbates this immune evasion through metabolic inflammation and adipokine-driven signaling. Recent studies have implicated CXC chemokines, particularly CXCL5, as central mediators in shaping the immune landscape of PDAC. In a pivotal study, Walsh <i>et al</i> delineated a novel mechanism wherein adipocyte-derived cytokines (interleukin-1β and tumor necrosis factor) induce tumor-derived CXCL5 expression, thereby promoting myeloid-driven immunosuppression in obese PDAC models. Their findings demonstrated that CXCL5 ablation enhances CD8⁺ T-cell infiltration yet paradoxically increases monocytic myeloid-derived suppressor cell accumulation and arginase-1 expression, underscoring the complexity of chemokine signaling. Notably, only combinatorial targeting of CXCL5 and programmed cell death protein-1 yields therapeutic benefit, emphasizing the necessity of multiaxis interventions. This commentary synthesizes the mechanistic insights and translational implications of these findings, highlighting CXCL5 as a pivotal node linking metabolic dysfunction to immune resistance and a promising target for combinatorial immunotherapy in PDAC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune checkpoint blockade and transarterial chemoembolization in liver-limited hepatocellular carcinoma: new questions at the dawn of a new era.","authors":"Aruj Dhyani, James J Harding","doi":"10.1136/jitc-2025-012658","DOIUrl":"10.1136/jitc-2025-012658","url":null,"abstract":"<p><p>Anti-programed cell death protein-1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies combined with anti-vascular endothelial growth factor (VEGF) or anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are now standard therapeutic options for patients with treatment-naïve, advanced stage, hepatocellular carcinoma. Given the observed efficacy in the advanced setting, the unmet need for therapies for intermediate stage liver cancer, and compelling preclinical rationale for combination with liver-directed therapies, such as transarterial chemoembolization, immunotherapies have quickly moved into earlier stages of the disease. Several phase 1/2 clinical trials have collectively verified the safety of immune checkpoint blockade with regional therapy for intermediate stage, liver-limited, hepatocellular carcinoma. Recently, two global, randomized, double-blind, placebo-controlled studies have demonstrated superior efficacy, based on the surogate of progession free survial, for transarterial chemoembolization plus combination immunotherapy over chemoembolization alone. In this issue of the <i>Journal</i>, Li and colleagues present data for an anti-PD-1 inhibitor with chemoembolization in liver-limited hepatocellular carcinoma (HCC). This study, along with the status of the field, provides the opportunity to highlight key issues for implementation of combinatorial approaches in patients with liver-limited liver cancer, which are discussed in this Commentary. Regional treatment with immune checkpoint inhibition combinations for intermediate stage disease is now rightly at the forefront of HCC drug development, though specific biologic factors, ideal patient characteristics, and optimal combinations require deeper investigation prior to routine use for all patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why has immune \"checkpoint\" therapy failed in most clinical trials?","authors":"Xuan Yang, Lieping Chen","doi":"10.1136/jitc-2025-012457","DOIUrl":"10.1136/jitc-2025-012457","url":null,"abstract":"<p><p>Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other 'checkpoint inhibitors' targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance-but not redundancy-of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}