Cancer immunology, immunotherapy : CII最新文献

{"title":"A novel oncolytic herpes simplex virus type 2 induces polarization of tumor-associated macrophages and remodels the immune microenvironment in glioblastoma.","authors":"Xin Yang, Shenglan Li, Yanjie Lan, Can Wang, Meng Zhang, Wenjing Zhao, Rong Zhang, Mengqian Huang, Zhuang Kang, Botao Zhang, Xiangyong Gu, Feng Chen, Zhen Wu, Binlei Liu, Wenbin Li","doi":"10.1007/s00262-026-04440-w","DOIUrl":"10.1007/s00262-026-04440-w","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor with limited survival despite multimodal therapy. Its profoundly immunosuppressive tumor microenvironment severely restricts treatment efficacy. Oncolytic viruses represent a promising therapeutic strategy, yet the immunological mechanisms underlying the antitumor activity of OH2 (oncolytic herpes simplex virus type 2) remain poorly defined.</p><p><strong>Methods: </strong>The effects of OH2 were evaluated in GBM cell lines (U251, LN229 and GL261) by assessing cell viability, migration, apoptosis, and cell cycle distribution. Modulation of tumor-associated macrophages (TAMs) was examined in RAW264.7 and THP-1 cells through functional assays, RNA sequencing, Western blotting and pharmacologic inhibition. In vivo studies were performed in subcutaneous and orthotopic GBM models to assess tumor growth and immune alterations. Exploratory clinical observations were conducted in seven recurrent GBM patients (NCT05235074), including peripheral blood monocyte profiling, longitudinal immune monitoring and cytokine analysis.</p><p><strong>Results: </strong>OH2 induced apoptotic and oncolytic cell death in GBM cells, while inhibiting cell proliferation and migration in vitro. In macrophage models, exposure to OH2-conditioned media enhanced proliferation and phagocytic activity and promoted M1-like polarization, accompanied by activation of JAK-STAT1 signaling. In vivo, OH2 suppressed tumor growth, promoted M1-like TAM polarization, reduced immunosuppressive macrophage populations, and increased recruitment of bone marrow-derived macrophages into the brain. Exploratory clinical observation suggested that changes in peripheral monocyte profiles may be associated with clinical benefit.</p><p><strong>Conclusions: </strong>OH2 exerts antitumor activity in GBM through direct oncolysis and immune microenvironment modulation, highlighting its potential as an immunotherapeutic strategy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13442803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148102496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics of cervical cancer reveals microenvironment shaped the malignant epithelial programs and ECM-associated immune niches.","authors":"Qing Chen, Jinli Lyu, Yu Li, Lei Zhang, Pingyue Zhao, Guanwen Gao, Yunfei Wang, Changzhong Li, Xiaowei Zhang","doi":"10.1007/s00262-026-04439-3","DOIUrl":"10.1007/s00262-026-04439-3","url":null,"abstract":"<p><strong>Objectives: </strong>Cervical cancer progression and therapeutic response are influenced by intratumoral heterogeneity and the tumor microenvironment. The diversity of malignant epithelial subtypes and their interactions with immune cells present significant challenges for effective clinical management.</p><p><strong>Methods: </strong>We applied Stereo-seq spatial transcriptomics to FFPE cervical cancer specimens to define malignant epithelial subpopulations via marker expression, functional enrichment, pseudotime trajectory inference, and transcription factor activity. Findings were validated using immunohistochemistry in CIN III and invasive carcinoma and public scRNA-seq dataset. Cell-cell communication and niche-specific ligand were performed using CellChat and NicheNet.</p><p><strong>Results: </strong>Four malignant epithelial programs were identified, including a proliferative ITGB6⁺ Epi, an invasive-edge ITGA6⁺ Epi enriched for EMT and matrix adhesion, a stress-adaptive NDRG1⁺/PVT1⁺ Epi at the tumor-stroma interface, and a differentiated TMPRSS11D⁺ Epi with barrier-like features. Pseudotime analysis revealed a unidirectional trajectory from ITGB6⁺ progenitor-like cells, diverging toward either ITGA6⁺ or NDRG1⁺ states, converging on TMPRSS11D⁺ differentiation. IHC confirmed stage-associated expression patterns, including ITGB6 upregulated in invasive carcinoma and ITGA6 enriched at invasive fronts. Comparable epithelial heterogeneity was observed in scRNA-seq data. Communication analyses showed broad mesenchymal-epithelial interactions dominated by extracellular matrix ligands, ITGA6⁺ epithelium displaying a distinct matrix-oriented communication signaling profile involving laminin-associated and TGFA-EGFR signaling. NicheNet further highlighted THBS1 as prominent microenvironmental signals predicted to regulate ITGA6-associated targets.</p><p><strong>Conclusions: </strong>Cervical cancer displays spatially organized epithelial heterogeneity shaped by distinct microenvironmental niches. The ITGA6⁺ epithelial program is closely linked to matrix interactions and THBS1-associated signaling, suggesting a role in invasion and immune modulation.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13442770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148059286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pertussis toxin-induced lymphocytosis shifts the tumor microenvironment toward immune activation via CXCL9 signaling.","authors":"Jae-Keun Cho, Kyungmin Lee, Da-Yong Shin, Truc Do Thanh Nguyen, Woongyang Park, Se Jin Im, Han-Sin Jeong","doi":"10.1007/s00262-026-04436-6","DOIUrl":"10.1007/s00262-026-04436-6","url":null,"abstract":"<p><strong>Background: </strong>A decrease in peripheral lymphocyte count in cancer patients predicts poorer prognosis and can be a useful discriminator in response to anti-tumor immunotherapy. However, therapeutic interventions to induce lymphocytosis and improve the efficacy of anti-tumor immunotherapy have not been investigated.</p><p><strong>Methods: </strong>In this study, we used pertussis toxin (PTX) to induce lymphocytosis; toxicity was minimal at controlled doses. Using an in vivo squamous cell carcinoma (SCC) model, the effects of PTX on anti-PD1 treatment efficacy were evaluated. To characterize the underlying changes associated with PTX pretreatment, we conducted immunohistochemistry, transcriptomic analysis, flow cytometry, and chemokine array analyses.</p><p><strong>Results: </strong>PTX increased lymphocyte counts in SCC-tumor-bearing mice and shifted tumors from low to high immune scores. PTX-induced elevation of CXCL9 led to lymphocytosis and increased immune cell infiltration in tumor tissues. Combining PTX with an anti-PD1 antibody significantly suppressed in vivo SCC tumor growth compared with anti-PD1 treatment alone. The combination treatment induced a greater proportion of T cells in the tumor microenvironment, and these findings were associated with increased terminally differentiated CD8⁺ T cells and higher Ki-67 expression. In addition, tumor-specific IFN-γ production was augmented in animals treated with anti-PD1 antibody and combination treatments, but not with PTX alone.</p><p><strong>Conclusions: </strong>PTX can induce high lymphocyte infiltration into the tumor microenvironment, creating a favorable immune environment for immune checkpoint inhibitors. These PTX actions could enhance the efficacy of anti-PD1 treatment in an in vivo SCC model.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148059314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flow-cytometric profiling of large extracellular vesicles as immunophenotypic biomarkers in head and neck squamous cell carcinoma.","authors":"Judith Büntzel, Markus Maulhardt, Alexander Casimir Angleitner, Matthias Schulz, Daniel Köberle, Said Naser, Clara Zwerenz, Charlotta Friederike Pagel, Andrea Hille, Anna-Carina Hund, Jens Büntzel","doi":"10.1007/s00262-026-04426-8","DOIUrl":"10.1007/s00262-026-04426-8","url":null,"abstract":"<p><strong>Background: </strong>Large extracellular vesicles (large EV) released from tumor and benign cells are detectable in blood and hold potential as non-invasive biomarkers. While their diagnostic relevance has been shown in several malignancies, their role in head and neck squamous cell carcinoma (HNSCC) remains insufficiently characterized.</p><p><strong>Methods: </strong>Large EV were isolated from peripheral blood of patients with HNSCC (n = 66), non-small cell lung cancer (NSCLC; n = 52; adenocarcinoma n = 39, squamous cell carcinoma (SQCCL) n = 11), and healthy controls (n = 11) by differential centrifugation. Flow cytometry quantified surface expression of EGFR, EPCAM, MUC1, and PD-L1. Associations with clinical parameters were analyzed using t-tests, Spearman correlations, logistic regression, and random forest modeling.</p><p><strong>Results: </strong>HNSCC-derived large EV showed significantly higher EGFR and MUC1, but lower EPCAM expression compared to controls. PD-L1 expression increased with advancing tumor stage and was positively associated with metastatic status, whereas EGFR levels declined in metastatic disease. Combined ROC analysis of EGFR, EPCAM, and PD-L1 yielded an AUC of 0.785 (p = 0.003), distinguishing HNSCC from controls. Comparative profiling revealed higher EGFR and EPCAM expression in HNSCC versus NSCLC, while MUC1 predominated in NSCLC, particularly in SQCCL; notably, the NSCLC cohort was predominantly adenocarcinoma. A marker panel comprising EGFR, EPCAM, and MUC1 differentiated HNSCC from SQCCL in this limited subgroup (n = 11) with 96.97% sensitivity, 45.45% specificity, 92.75% positive predictive value and 75.00% negative predictive value.</p><p><strong>Conclusion: </strong>Flow-cytometric profiling of circulating large EV provides a feasible liquid biopsy approach for tumor characterization in HNSCC. PD-L1 expression reflects tumor burden, and combined large EV marker analysis enables differentiation between HNSCC and primary squamous lung carcinoma, supporting its diagnostic utility in clinical oncology.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13221563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IAR025, a novel anti-DLL3 x CD3-bispecific antibody, displays high antitumor efficacy in preclinical models of small-cell lung cancer.","authors":"Yang Liu, Lei Cao, Mengqiu Xu, Ninghuan Li, Jian Zhang, Mengjia Zhu, Zhihui Kuang, Huijun Sha, Min Wu, Jinling Xu, Zhihai Wu, Ye Feng, Li Li","doi":"10.1007/s00262-026-04416-w","DOIUrl":"10.1007/s00262-026-04416-w","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its high expression on SCLC but limited expression on normal tissues. Here, we developed a bispecific T cell engager, IAR025, and investigated its antitumor efficacy against SCLC. IAR025 has a CD3 arm for T cell activation and a DLL3 arm for recognizing tumor cells with optimal affinity and binding domain. IAR025 resulted in a dose-dependent eradication of DLL3-positive SCLC cells, without nonspecific cell destruction in DLL3-negative cells in vitro. Administration of IAR025 in DMS79 and SHP-77 humanized mouse models significantly inhibited tumor growth. The mechanism study revealed that IAR025 treatment led to increased T-cell recruitment in tumors. IAR025 activity was further enhanced when combined with chemotherapy or anti-PD-1 treatment. In cynomolgus monkeys, IAR025 was well-tolerated at a dose up to 10 mg/kg and exhibited linear pharmacokinetics with a half-life of 90 h. Collectively, these preclinical results demonstrate that IAR025 is a highly potent therapeutic strategy for treating SCLC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148038966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enterotype-specific microbial biomarkers of immune checkpoint inhibitor response revealed by large-scale integrated metagenomic analysis.","authors":"Francesco Candeliere, Enrico Busi, Sara Cerri, Laura Sola, Matteo Lombardi, Stefano Greco, Sara Pedroni, Alberto Amaretti, Stefano Raimondi, Chiara Chiavelli, Maria Giuseppa Vitale, Federica Bertolini, Roberta Depenni, Giorgia Franchini, Massimo Dominici, Maddalena Rossi","doi":"10.1007/s00262-026-04432-w","DOIUrl":"10.1007/s00262-026-04432-w","url":null,"abstract":"<p><p>The gut microbiota appears to play a critical role in modulating antitumor immune responses and influencing the efficacy of cancer immunotherapy drugs such as immune checkpoint inhibitors. However, the identification of consistent microbial biomarkers of response remains a significant challenge. This lack of consensus is largely driven by multi-source heterogeneity, including geographic variations in lifestyle, and high inter-individual variability. We hypothesize that these inconsistencies arise because microbiome composition is not uniform but organized into distinct enterotypes. To address this, we performed an integrated metagenomic analysis of 569 fecal samples from oncological patients affected by different tumor types treated with immunotherapy. The samples were clustered into two main enterotypes, E1 and E2, each of them containing two subclusters. A total of 166 species (e.g., Collinsella spp., Blautia spp., Bacteroides spp.) were identified as enterotype-specific biomarkers. A preliminary independent concordance assessment of these biomarkers was conducted in 19 oncologic patients with exceptional response to immunotherapy, providing an initial confirmation of selected enterotype-associated signals. Furthermore, we evaluated the predictive potential of gut microbiota profiles for immunotherapy outcomes through machine learning techniques. The models showed encouraging, albeit moderate, performance in the heterogeneous full dataset, supporting the potential of microbiome-based stratification as an exploratory framework for patient classification, while indicating that further validation is needed before clinical application.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world efficacy and safety of immune checkpoint blockades in advanced urothelial carcinoma with histologic variant subtypes: the pembroblad study.","authors":"Karim Amrane, Luca Campedel, Fabien Moinard-Butot, Mathilde Gout, Hakim Mahammedi, Mostefa Bennamoun, Tressie Herrmann, Pierre-Etienne Gabriel, Damien Pouessel, Matthieu Roulleaux-Dugage, Constance Thibault, Mathilde Cancel, Aude Flechon, Olivier Huillard, Baptiste Abbar, Delphine Borchiellini, Louis Doublet, Laëtitia Augusto-Pelegrin, Elouen Boughalem, Pierre Cornillon, Clément Dumont, Philippe Barthélémy","doi":"10.1007/s00262-026-04421-z","DOIUrl":"10.1007/s00262-026-04421-z","url":null,"abstract":"<p><strong>Background: </strong>Histologic variants (HV) of urothelial carcinoma (UC-V) and non-urothelial carcinomas (NUC) of the bladder and urinary tract are aggressive malignancies with poor prognosis and limited response to platinum-based chemotherapy. Despite their biological particularities and distinct immune microenvironments, these HV subtypes are under-represented in immune checkpoint blockade (ICB) trials.</p><p><strong>Methods: </strong>PEMBROBLAD is a French national multicenter retrospective study conducted across 24 centers. We included patients with advanced UC-V or NUC who received second-line anti-PD-(L)1 monotherapy after progression on platinum-based chemotherapy between 2016 and 2022. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.</p><p><strong>Results: </strong>We included 129 UC-V and 34 NUC. With a median follow-up was 21.9 months, the median OS was 8.6 [95% confidence interval (CI), 5.3-11.2] months, with 8.5 [95% CI 5.3-10.9] months for UC-V and 10.5[95% CI 3.5-22.8] months for NUC. The median PFS was 2.6 [95% CI 2.1-3.4] months with 2.5 [95% CI 2.0-3.4] months for the UC-V group and 2.6 [2.0-3.4] months for the NUC group. ORR was 31.4% overall (complete response 15.3%, partial response 16.1%). In multivariable analysis, ECOG performance status ≥ 2 was independently associated with both poorer OS (HR 3.30, 95% CI 1.22-8.92; p = 0.018) and PFS (HR 2.32, 95% CI 1.52-3.54; p < 0.001). Pembrolizumab treatment was associated with improved PFS (HR 0.53, 95% CI 0.31-0.81; p = 0.017). Grade ≥ 3 immune-related adverse events occurred in 10.8% of patients, with no treatment-related deaths.</p><p><strong>Conclusions: </strong>Anti-PD-(L)1 monotherapy shows clinical benefit in advanced UC-V and NUC after platinum failure.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the Wnt5A pathway in resistance to immune checkpoint inhibitors in advanced Non-Small Cell Lung Cancer.","authors":"Paul Takam Kamga, Adrien Costantini, Claude Capron, Mathieu Glorion, Catherine Julie, Jean-François Emile, Étienne Giroux-Leprieur","doi":"10.1007/s00262-026-04437-5","DOIUrl":"10.1007/s00262-026-04437-5","url":null,"abstract":"<p><strong>Background: </strong>β-catenin-independent Wnt signaling plays a role in lung carcinogenesis, but its impact on prognosis and immune response in Non-Small Cell Lung Cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICI) remains unclear. This study evaluates the prognostic significance of Wnt5a and Wnt5b and their role in immune modulation.</p><p><strong>Methods: </strong>A prospective cohort of 52 consecutive advanced NSCLC patients receiving first-line ICI therapy was analyzed. Plasma samples were analysed using ELISA to quantify Wnt5a/Wnt5b. PBMCs were stimulated with PHA ± Pembrolizumab and co-cultured with recombinant Wnt5a or NSCLC explants. Wnt signaling inhibition was achieved using porcupine inhibitors (IWP-2/IWP-4) or neutralizing Wnt5a antibody. CD8 + T cell activation and cytokine production (INFγ, IL-6, IL-10) were measured by flow cytometry and ELISA.</p><p><strong>Results: </strong>We observed that Wnt5a levels were significantly elevated in NSCLC patients and correlated with poor tumor response (RR = 2.4, p = 0.05) and shorter progression-free survival (Hazard Ratio (HR) = 2.77; 95% CI 1.11-6.88; p = 0.028.). In vitro, Wnt5a suppressed CD8 + T cell activation and INFγ production. These immunosuppressive effects were reversed by Wnt5a inhibitors, highlighting their potential as therapeutic agents to improve immune response in NSCLC patients receiving ICI therapy.</p><p><strong>Conclusions: </strong>Overall, high Wnt5a correlates with immune suppression and poor ICI response, suggesting its potential as a predictive biomarker and therapeutic target in NSCLC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β inhibition enhances anti-tumor immunity and sensitizes PD-1 blockade therapy of bone marrow-derived myofibroblasts-induced \"immunotherapy resistance\" tumor model.","authors":"Xin Cheng, Lina He, Cong Zhou, Qingli Li, Baiwen Zhang, Jianzheng Wang, Xiaojiao Cheng, Shuiping Tu","doi":"10.1007/s00262-026-04428-6","DOIUrl":"10.1007/s00262-026-04428-6","url":null,"abstract":"<p><p>Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous tumors formed by a mixture of bone marrow-derived myofibroblasts (BMFs) and tumor cells not only grew faster than those formed by tumor cells alone but were also resistant to ICB therapy. However, the specific mechanism by which BMFs mediate this immune resistance remained unclear. In this study, we established a \"BMF + MC38\" mixed-cell subcutaneous tumor model to further validate its ICB therapy-resistant phenotype, investigate the mechanism underlying BMF-mediated immune resistance, and explore potential therapeutic strategies for this \"immune-excluded\" type of tumor. Our findings revealed that \"BMF + MC38\" mixed-cell subcutaneous tumors lost sensitivity to anti-PD-1 antibody treatment. Furthermore, these mixed-cell subcutaneous tumors exhibited significantly impaired CD8+ T cell infiltration and function, along with an increased proportion of regulatory T cells (Tregs). Higher expression of TGFβ1 was detected in the mixed-cell tumors compared to the MC38 cell tumors. Importantly, either reducing BMF-derived TGFβ1 expression or concurrently targeting PD-1 and TGFβ effectively restored the sensitivity to PD-1 blockade, rescued CD8+ T cell infiltration and function. Additionally, this study revealed that simultaneously targeting PD-1, TGFβ, and VEGFR further suppressed the growth of these mixed-cell subcutaneous tumors. These findings provide a viable combination targeted therapy strategy for the clinical treatment of solid tumors that are insensitive to immunotherapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GFI1 enhances MHC-I expression in tumor cells and augments tumor responsiveness to PD-1/PD-L1 inhibitors.","authors":"Yu Xi, Kewei Xiao, Kelin Meng, Taiyan Yu, Tianlai Wang, Xu Wang, Ounan Pan, Chenxi Zeng, Xue Wang, Xiangning Fu, Lequn Li","doi":"10.1007/s00262-026-04430-y","DOIUrl":"10.1007/s00262-026-04430-y","url":null,"abstract":"<p><strong>Background: </strong>Growth factor-independent-1 transcription repressor (GFI1) is crucial for determining the differentiation and fate of exhausted CD8⁺ T cells and affects immunotherapy outcomes. However, the effects of tumor cell-intrinsic GFI1 on antitumor immunity and the response to immunotherapy remain unknown.</p><p><strong>Methods: </strong>The tumor cell-intrinsic expression of GFI1 was examined via RT‒qPCR and Western blotting. Immunohistochemical staining of tumor tissues was performed to assess the relationships among GFI1, CD8, and MHC I expression. A syngeneic mouse model and clinical tumor samples from NSCLC patients undergoing immunochemotherapy were used to evaluate how tumor cell-intrinsic GFI1 affects the response to immunotherapy. Additionally, techniques such as flow cytometry, immunoprecipitation, ChIP-qPCR, immunofluorescence, and both loss- and gain-of-function approaches were employed to investigate the underlying mechanisms involved.</p><p><strong>Results: </strong>Tumor-intrinsic GFI1 expression was positively associated with MHC I expression and the infiltration of CD8⁺ T cells. Tumors with higher GFI1 levels showed a significantly better response to immunotherapy. The overexpression of GFI1 in tumor cells increases MHC-I expression in a STAT1-dependent manner. Mechanistic analysis revealed that GFI1 inhibits HDAC1 activity in tumor cells by promoting its export to the cytoplasm, thereby increasing H3K9 acetylation and the transcription of STAT1 and MHC-I. Additionally, phenformin, an AMPK activator, increases GFI1 levels by downregulating EZH2 expression. Compared with anti-PD-L1 therapy alone, combining phenformin with anti-PD-L1 therapy enhances antitumor effects.</p><p><strong>Conclusions: </strong>This study demonstrated the crucial role of tumor-intrinsic GFI1 in enhancing antitumor immune responses, suggesting a new target for increasing the effectiveness of PD-1/PD-L1 blockade.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}