Journal for Immunotherapy of Cancer最新文献

{"title":"TAMing the tumor: targeting immune inhibitory receptors on tumor-associated macrophages in pediatric brain tumors - an emerging immunotherapy strategy.","authors":"Lieke Mooij, Joyce I Meesters-Ensing, Friso G Calkoen, Jasper van der Lugt, Linde Meyaard, Stefan Nierkens, Tiago Carvalheiro","doi":"10.1136/jitc-2026-015513","DOIUrl":"10.1136/jitc-2026-015513","url":null,"abstract":"<p><p>Brain tumors are the most common solid tumors in children. Despite recent advancements in cancer survival, the prognosis for high-grade pediatric brain tumors remains poor, with treatments resulting in severe long-term side effects. Over the last decade, immune checkpoint blockade (ICB) has emerged as a promising treatment strategy, with success across various tumor types, particularly in adult malignancies. However, its efficacy in pediatric brain tumors has been limited, which can be attributed to the unique characteristics of the brain tumor microenvironment (TME), including a low mutational burden, restricted T cell infiltration, and immunosuppressive milieu. Importantly, clinically approved ICBs primarily target T cell-associated pathways, thereby neglecting other dominant immune populations within the TME.Among these, tumor-associated macrophages (TAMs) often represent the most abundant immune cell compartment within pediatric brain tumors. TAMs consist of resident microglia and infiltrating bone marrow-derived macrophages and play a central role in establishing and maintaining an immunosuppressive environment. They promote tumor progression, suppress cytotoxic T cell activity, and contribute to therapeutic resistance. However, they are highly heterogeneous, and their phenotype and functions are regulated by the surrounding TME. This intrinsic plasticity makes them promising therapeutic targets: rather than solely attempting to enhance T cell activity, reprogramming TAMs may fundamentally remodel the immune landscape of pediatric brain tumors.In this context, immune inhibitory receptors emerge as critical regulators of TAM function. While traditionally studied in T cells, inhibitory receptors expressed on macrophages influence phagocytosis, cytokine production, antigen presentation, and polarization states. Emerging preclinical evidence indicates that targeting inhibitory receptors on TAMs can shift macrophages from suppressive toward pro-inflammatory phenotypes, enhance phagocytosis, and improve survival in brain tumor models. Nevertheless, the expression patterns and functional consequences of these receptors in pediatric brain TAMs remain incompletely characterized.In this review, we examine the role of immune inhibitory receptors on TAMs in pediatric brain tumors and discuss how targeting these pathways may reprogram the TME, enhance antitumor immunity, and provide new therapeutic avenues for this challenging group of malignancies. Unlike most pediatric brain tumor immunotherapy reviews, this review specifically evaluates myeloid-targeted inhibitory receptor pathways in the pediatric brain tumor context.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906164","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":"Transcriptomic analysis of a phase 1 trial for intraperitoneal monocytes plus IFNs in ovarian cancer reveals support and recruitment of cell-mediated immunity.","authors":"Franklin Ning, Emily San Andres-Montalvan, Thomas J Meyer, Sabina Kaczanowska, Rosie Kaplan, Christina M Annunziata","doi":"10.1136/jitc-2026-014938","DOIUrl":"10.1136/jitc-2026-014938","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer is the most lethal gynecological malignancy and lacks therapeutic options in the recurrent setting. We previously determined the safety and initial clinical activity of intraperitoneal autologous monocytes with interferon gamma and interferon alpha (AMIGA) in women with recurrent, platinum-resistant ovarian cancer, but not all enrolled patients showed benefit, warranting further analysis to understand and improve this therapy.</p><p><strong>Experimental design: </strong>Bulk RNA sequencing and single-cell RNA sequencing were conducted on circulating immune cells from patients with ovarian cancer treated with AMIGA. Primary human monocytes and T cells were isolated from healthy donors and used in co-cultures with ovarian cancer cell lines to test the effects of AMIGA on T-cell recruitment.</p><p><strong>Results: </strong>Comparing circulating immune cells from long-term responders to non-responders from our clinical trial revealed an increased cell-mediated immune response in long-term responders. T cells in AMIGA-treated patients also upregulated unique, specific T cell receptor-beta chain genes. Bulk RNA-seq of peripheral blood mononuclear cells revealed AMIGA-driven upregulation of CXCL10 and CCL2 mRNA. An increase in these chemokines was consistently reflected in patients' malignant ascites. Finally, in vitro models validated increases in CXCL10 as well as CCL2, and demonstrated that these chemokines exert variable effects on T-cell chemotaxis.</p><p><strong>Conclusions: </strong>The AMIGA-driven effects on T cell recruitment and upregulation of specific T cell receptor-beta chain genes support the development of future combination therapies of intraperitoneal AMIGA and T cell-based immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906122","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":"Evaluating the potential of candidate surrogate endpoints for overall survival in treatment-naive metastatic melanoma treated with anti-PD-1-based regimens with or without anti-CTLA-4 therapy.","authors":"Pierre Squifflet, Everardo D Saad, Murat Kurt, James Larkin, Peter Mohr, Andriy Moshyk, Marc Buyse","doi":"10.1136/jitc-2026-016440","DOIUrl":"10.1136/jitc-2026-016440","url":null,"abstract":"<p><strong>Background: </strong>Using surrogates for overall survival (OS) may expedite the development of, and patient access to, novel treatments. We assessed potential surrogates for OS in patients with metastatic melanoma treated with nivolumab-containing regimens in the first-line treatment setting.</p><p><strong>Methods: </strong>We used individual-patient data from 1865 patients enrolled in four randomized controlled trials studying single-agent nivolumab or combinations of nivolumab and ipilimumab against dacarbazine or immunotherapy. Using the two-level meta-analytic framework, we evaluated three candidate surrogates: objective response rate (ORR), progression-free survival (PFS), and time to next treatment or death (TNTD). We measured the patient-level associations between candidates and OS using ORs in the case of ORR and Spearman's correlation coefficient (ρ) in the case of time-to-event surrogate endpoints. We used R² to measure the trial-level association between ORs or HRs for each surrogate and the HRs for OS.</p><p><strong>Results: </strong>For ORR, at the individual-level, OR of survival was equal to 12.29 (95% CI 9.78 to 14.80), and at the trial-level R² was equal to 0.62 (95% CI 0 to 1.00). For PFS, at the individual-level ρ was equal to 0.72 (95% CI 0.70 to 0.73), and at the trial-level R² was equal to 0.73 (95% CI 0.27 to 1.00). For TNTD, at the individual-level ρ was equal to 0.77 (95% CI 0.76 to 0.78), and at the trial-level R² was equal to 0.77 (95% CI 0.37 to 1.00). In cross-validation, the 95% prediction intervals for HRs for OS predicted by regression models always contained the observed HRs for OS, indicating the stability of the models.</p><p><strong>Conclusion: </strong>At the individual-level, ORR exhibited a strong correlation with OS, whereas PFS and TNTD showed a moderate level correlation with OS. At the trial level, the key requirement for validating surrogates, all candidate surrogates demonstrated moderate predictive abilities for OS in future trials. These findings should be interpreted within the context of anti-PD-1-based therapies, with or without anti-CTLA-4 combinations, consistent with the trial evidence base included in this study.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891301","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 habitat radiomics predicts tertiary lymphoid structure status and identifies an IDO1⁺ migratory dendritic cell axis in breast cancer.","authors":"Yushuai Yu, Qing Wang, Yidan Lin, Kaiyan Huang, Ruijuan Wang, Junxiao Wang, Xiewei Huang, Jie Zhang, Weiwei Chen, Ruiliang Chen, Xuejun Chen, Fan Meng, Hengyu Zhang, Junhui Yuan, Jianqing Lin, Chuangui Song","doi":"10.1136/jitc-2026-015224","DOIUrl":"10.1136/jitc-2026-015224","url":null,"abstract":"<p><strong>Background: </strong>Tertiary lymphoid structures (TLS) are spatially organized immune niches associated with therapeutic response and favorable outcomes in breast cancer (BC). However, TLS assessment currently relies on invasive tissue-based analyses, and the biological mechanisms underlying imaging-based TLS prediction remain poorly understood.</p><p><strong>Methods: </strong>We developed and validated a spatial heterogeneity-based radiomic TLS signature (shTLS) using dynamic contrast-enhanced MRI to non-invasively predict TLS status across multicenter BC cohorts. Spatial habitat radiomics were used to capture intratumoral and peritumoral immune-related heterogeneity. Integrated multi-omics analyses, including transcriptomics, pathomics, genomics, single-cell RNA sequencing, immunohistochemistry, and multiplex immunofluorescence, were performed to biologically interpret shTLS-defined subgroups. Functional drug-sensitivity assays were conducted to assess therapeutic implications.</p><p><strong>Results: </strong>The shTLS model achieved robust predictive performance across independent cohorts and molecular subtypes. High shTLS scores were associated with immune-inflamed tumors characterized by spatially clustered activated T cells and dendritic cells (DCs). In contrast, shTLS-low tumors exhibited an immunosuppressive spatial niche with peripheral accumulation of CD4⁺ PD-1⁺ T cells and plasma cells, increased immune-tumor separation, and enhanced inflammatory and immunoregulatory signaling. An indoleamine 2,3-dioxygenase 1 (IDO1)-associated immunoregulatory program was observed in the shTLS-low tumors, which appeared to be preferentially expressed by LAMP3⁺CCR7⁺ migratory DCs. Pharmacologic inhibition of IDO1 enhanced chemotherapy and CDK4/6 inhibitor sensitivity in vitro.</p><p><strong>Conclusion: </strong>This study establishes spatial radiomics as a non-invasive approach to decode TLS-associated immune ecosystems and supports the presence of an IDO1-associated immunosuppressive phenotype, providing biological insight and translational rationale for patient stratification and future combination strategies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887552","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":"Targeting the PD-L1-induced PDK4/GLS metabolic axis overcomes anti-PD-1 resistance in non-small cell lung cancer.","authors":"Wenxin Lian, Hui Yang, Yuqi Zhang, Chenchen Liu, Chunyao Fang, Mengyue Xu, Yixing Yang, Yan Wang, Runqiu Jiang, Jing Xu, Wen Gao","doi":"10.1136/jitc-2026-015037","DOIUrl":"10.1136/jitc-2026-015037","url":null,"abstract":"<p><strong>Background: </strong>Metabolic reprogramming within the tumor microenvironment is a pivotal barrier to effective immune checkpoint blockade (ICB). While programmed death ligand 1 (PD-L1) is well characterized as a ligand inhibiting T-cell function, its intrinsic 'reverse signaling' role in regulating tumor metabolism and shaping the immune landscape remains poorly understood. Here, we investigated the metabolic determinants of resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy and the underlying molecular mechanisms.</p><p><strong>Methods: </strong>Integrated metabolomics and transcriptomics were performed on tumor samples from patients with non-small cell lung cancer and cell lines. Mechanisms were delineated using RNA sequencing, cleavage under targets and tagmentation assays, metabolic flux analysis, and coculture systems. The therapeutic efficacy of targeting metabolic effectors was evaluated in syngeneic mouse models and correlated with immune profiling.</p><p><strong>Results: </strong>We identified a distinct metabolic signature characterized by aberrant pyruvate accumulation in patients resistant to anti-PD-1 therapy. Mechanistically, we demonstrate that antibody-mediated ligation of PD-L1 triggers an intrinsic endoplasmic reticulum (ER) stress response via the PERK-ATF4-CHOP axis. ATF4 acts as a transcriptional activator that directly upregulates pyruvate dehydrogenase kinase 4 (PDK4) (blocking pyruvate oxidation) and glutaminase (GLS) (promoting glutaminolysis), creating a 'dual-hit' metabolic rewiring that drives intracellular pyruvate build-up. Subsequently, tumor-secreted pyruvate is taken up by tumor-associated macrophages (TAMs) via MCT1, inducing mitochondrial reactive oxygen species accumulation and driving them into a state of cellular senescence. These senescent TAMs upregulate PD-L1 via STAT3 signaling, thereby reinforcing an immunosuppressive feedback loop. Pharmacological inhibition of PDK4 and GLS effectively abolished pyruvate accumulation, prevented macrophage senescence, and restored CD8+ T-cell cytotoxicity.</p><p><strong>Conclusions: </strong>Our study identifies a novel 'PD-L1-ER stress-pyruvate-macrophage senescence' axis as a key mechanism underlying primary resistance to ICB. These findings highlight the non-canonical reverse-signaling function of PD-L1 in metabolic remodeling and propose that targeting the PDK4/GLS-dependent pyruvate surge offers a promising therapeutic strategy to sensitize tumors to anti-PD-1 immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880454","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":"GTPase RAB31 supports ANXA1-driven macrophage education through clathrin-mediated endocytosis to suppress antitumor immunity.","authors":"Jingjing Liu, Shanshan Wang, Dengyi Bao, Ge Dong, Yunxi Ma, Guorong Zhang, Xin Liu, Dongli Zhang, Lulu Wang, Shuqian Xu, Zhigang Cai","doi":"10.1136/jitc-2026-015703","DOIUrl":"10.1136/jitc-2026-015703","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs) play pivotal roles in shaping the tumor-microenvironment (TME) through functional plasticity, which is regulated by extrinsic and intrinsic signals. However, the role of vesicular trafficking in TAMs remains poorly understood. RAB31, a small GTPase enriched in myeloid cells, was proposed as a potential regulator of TAM polarization through clathrin-mediated endocytosis (CME). We hypothesized that RAB31 modulates TAM education by tumor-derived signals and thereby shapes antitumor immunity.</p><p><strong>Methods: </strong>We profiled RAB31 expression in human cancers using public single-cell RNA sequencing (scRNA-seq) datasets and clinical sample immunofluorescence staining. Rab31 knockout mice were employed in subcutaneous tumor models. The TME was profiled by scRNA-seq, bulk RNA-seq, and flow cytometry. Bone marrow transplantation, adoptive cell transfer, and antibody-mediated depletion were performed to identify the effector cell populations. Co-immunoprecipitation coupled with mass spectrometry, receptor half-life assays, inhibitor intervention and lysosomal colocalization experiments dissected the molecular mechanism. Functional T-cell chemotaxis, activation, and anti-programmed death-ligand 1 (PD-L1) response assays were performed.</p><p><strong>Results: </strong>RAB31 was highly expressed in TAMs across multiple cancers and correlated with poor prognosis and immunosuppressive TME. Rab31 deficiency reprogrammed TAMs to M1-like phenotype, enhanced CD8⁺ T-cell infiltration and activation, and suppressed tumor growth. Mechanistically, Rab31 preserves FPR2 cell surface stability through a CME-dependent mechanism; its loss redirected FPR2 to lysosomal degradation, disrupted tumor-derived ANXA1 signaling, and unleashed NF-κB activity. Rab31 deficiency synergized with anti-PD-L1 therapy in a CD8⁺ T cell-dependent manner.</p><p><strong>Conclusions: </strong>These findings establish the CME/RAB31 pathway as an indispensable regulator of TAM polarization, underscoring the pivotal role of vesicular trafficking in the TME.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880468","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":"LIM and SH3 protein 1 deficiency confers resistance to cytotoxic lymphocyte-mediated lysis and immunotherapy in gastric cancer by disrupting cytoskeleton dynamics.","authors":"Teming Zhang, Yingying Sun, Chao Chen, Jingwei Zheng, Liyun Chang, Yizhen Xiang, Qiongying Zhang, Haoliang Li, Wangkai Xie, Qiaoyi Xu, Chenchen Mao, Mingdong Lu, Zhenzhai Cai, Xian Shen, Xiangyang Xue, Zheng Han","doi":"10.1136/jitc-2025-014475","DOIUrl":"10.1136/jitc-2025-014475","url":null,"abstract":"<p><strong>Background: </strong>A substantial amount of research has been dedicated to the mechanisms by which tumor cells evade immune system recognition and manipulate the immune microenvironment to facilitate immune escape. Recent studies have shown that viruses and tumors can protect themselves from immune cytotoxicity by remodeling the actin cytoskeleton. However, cytoskeleton-mediated immune resistance and the specific cytoskeleton-related proteins involved require further research.</p><p><strong>Methods: </strong>Single-cell RNA sequencing was used to identify cytoskeleton-related genes associated with the response to anti-programmed cell death protein 1 (PD-1) therapy across four digestive tumors. Immunohistochemistry was used to detect LASP1 expression in gastric cancer and analyze its prognostic value for survival and anti-PD-1 response. The impact of LASP1 deficiency on tumor response to anti-PD-1 treatment and cytotoxic lymphocyte-mediated lysis was determined in vivo and in vitro. Live-cell imaging was used to compare actin cytoskeletal dynamics at the immunological synapse between LASP1-deficient and mock tumor cells. Molecular mechanisms underlying LASP1-mediated immune-resistance were dissected using co-immunoprecipitation, immunofluorescence, domain deletion complementation, and Laurdan staining.</p><p><strong>Results: </strong>The deficiency of LASP1 in gastric cancer affected the sensitivity of tumor cells to immunotherapy and induced cytotoxic lymphocytes exhaustion. LASP1 may act as a scaffold protein to regulate the Arp2/3 complex and remodel the cytoskeleton at the immunological synapses. LASP1 deficiency in tumor cells impairs lytic immunological synapse function by disrupting cytoskeletal dynamics-mediated cell membrane lipid organization at the immunological synapse. Finally, simvastatin combined with anti-PD-1 therapy reversed immunotherapy resistance in LASP1-deficient tumors.</p><p><strong>Conclusions: </strong>The deficiency of LASP1 in tumors mediates immunological synapse dysfunction by affecting cytoskeletal dynamics-mediated cell membrane lipid organization, thus enabling tumors to protect themselves from immune cytotoxicity and immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880399","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":"Overall survival of immunotherapy versus standard of care in chemorefractory microsatellite stable metastatic colorectal cancer: a propensity score matched analysis of 708 patients.","authors":"Guglielmo Vetere, Emerik Osterlund, Mahmoud M G Yousef, Songwit Payapwattanawong, Giulia Maddalena, Jumanah Alshenaifi, Kristin D Alfaro, Mark Knafl, Van K Morris, Christine M Parseghian, Kanwal P S Raghav, Robert A Wolff, Arvind Dasari, Michael J Overman, Scott Kopetz, John Paul Shen","doi":"10.1136/jitc-2026-015414","DOIUrl":"10.1136/jitc-2026-015414","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). However, selected patients with specific metastatic patterns may derive benefit.</p><p><strong>Methods: </strong>Patients with chemorefractory pMMR/MSS mCRC treated with ICI-based regimens were retrospectively identified. A comparison cohort treated with trifluridine/tipiracil±bevacizumab, regorafenib, or fruquintinib as standard of care (SOC) was generated through 1:1 propensity score matching by age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastases (present/absent), and RAS/BRAF status. Overall survival (OS) was compared using Cox regression.</p><p><strong>Results: </strong>A total of 354 patients treated with ICIs and 354 treated with SOC were matched. Median age was 55 years, 52% male, 32% ECOG PS 0, 30% right-sided, and 69% RAS mutated in both groups, while 61% and 60% had liver metastases, respectively. Median OS (mOS) was 10.8 months with ICIs and 9.0 months with SOC (HR 0.76, 95% CI 0.64 to 0.92, p=0.004). In patients without liver metastases, mOS was longer with ICIs than SOC (19.1 vs 13.2 months, HR 0.59, 95% CI 0.43 to 0.80, p<0.001), whereas outcomes were similar in patients with liver metastases (6.4 vs 6.5 months, p=0.303). In univariable analyses, age, sex, primary tumor site, and <i>RAS</i>/<i>BRAF</i> status were not associated with OS. Treatment with ICIs, absence of liver metastases, one prior line of therapy, less than three metastatic sites, and ECOG PS 0 were associated with the most favorable outcomes in univariable and multivariable models.</p><p><strong>Conclusions: </strong>In chemorefractory pMMR/MSS mCRC without liver metastases, ICI-based regimens yielded longer OS than SOC. Further investigation of ICIs in this patient population is warranted.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880433","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":"Mechanistic modeling of tumor immune microenvironment reveals strategies to enhance antibody-drug conjugates' efficacy.","authors":"Constantinos Harkos, Lance L Munn, Triantafyllos Stylianopoulos, Rakesh K Jain","doi":"10.1136/jitc-2026-015357","DOIUrl":"10.1136/jitc-2026-015357","url":null,"abstract":"<p><strong>Background: </strong>Antibody-drug conjugates (ADCs) and bispecific antibodies represent a rapidly advancing frontier in oncology, yet the abnormal tumor microenvironment (TME) hinders their delivery and reduces efficacy. Emerging immunomodulatory ADCs (IM-ADCs) demand mechanistic mathematical models that couple drug transport with immune dynamics.</p><p><strong>Methods: </strong>Here, we present a mechanistic framework for the delivery of HE-S2 ADC, an anti-programmed cell death ligand 1 (PD-L1) antibody bearing the bifunctional immunomodulator D18. Our model integrates cancer-immune cells interactions, TME properties, such as dysfunctional vessels, elevated interstitial fluid pressure, tissue hydraulic conductivity, and vascular permeability, spatiotemporal distributions across growing tumor and adjacent host tissue, convective-diffusive transport, ADCs binding and internalization kinetics and tumor-draining lymph node biology governing antigen presentation and the generation of effector CD8⁺ T cells. Parameters were calibrated simultaneously with the murine MC38 and B16 tumor growth data and effector CD8+T cell data following treatment with D18, anti-PD-L1, and ADC.</p><p><strong>Results: </strong>Our mechanistic spatiotemporal model captures the superior antitumor efficacy of the HE-S2 ADC relative to its individual components and provides mechanistic predictions for unmeasured variables, such as spatiotemporal dynamics of drug/immune-cell distributions. It explains reduced intratumoral D18 exposure via rapid clearance, while antibody/ADC achieves higher tumor retention through leaky tumor vasculature. The model suggests a reinforcing loop in which improved ADC exposure enhances CD8+T cell infiltration, driving tumor shrinkage that lowers fluid pressure and improves drug delivery. Parametric analyses findings support TME normalization strategies that increase functional vessel density prior to ADC administration; however, such approaches should preserve sufficient vascular permeability by maintaining vessel pore radius >~40 nm, ensuring pores remain large enough for ADC extravasation and effective intratumoral delivery.</p><p><strong>Conclusion: </strong>The proposed mechanistic model successfully captures how TME properties regulate the delivery and efficacy of IM-ADCs while suggesting TME normalization as a potential strategy to improve treatment outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874094","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":"Normal-immunopeptidome denominator: a safety atlas for immunotherapies targeting non-canonical and aberrantly expressed tumor antigens.","authors":"Li-Zhen Chen","doi":"10.1136/jitc-2026-016056","DOIUrl":"10.1136/jitc-2026-016056","url":null,"abstract":"<p><p>Proteogenomic cancer antigen discovery now extends beyond somatic mutations to include unmutated, aberrantly expressed, and non-canonical sources. We distinguish two orthogonal dimensions: molecular origin (canonical or non-canonical) and normal-tissue distribution (tumor-specific antigen, tumor-associated antigen, or lineage-specific antigen). Importantly, non-canonical origin does not imply tumor specificity. For human leukocyte antigen (HLA)-restricted immunotherapy, selectivity must be established at the level of naturally presented peptide-HLA (pHLA) complexes rather than inferred from RNA expression or total protein abundance. We therefore propose a normal-immunopeptidome denominator: a context-aware atlas of benign pHLA ligands that can be used to exclude unsafe candidates before therapeutic nomination. However, this denominator is necessary but not sufficient. Candidate nomination also requires evidence of analytical confidence, natural presentation on tumor cells, and, where available, peptide abundance and tumor heterogeneity. Additional considerations include whether the target is patient-specific or shared, its functional selectivity, the potential for immune escape, receptor cross-reactivity, HLA alloreactivity, and the modality-specific therapeutic index. We present a tiered framework that distinguishes core requirements, risk-triggered evaluation criteria, and recommended enhancements. These requirements escalate as uncertainty increases. Importantly, the absence of a peptide from existing databases should not be interpreted as evidence of its absence in humans.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874060","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}