Cancer immunology, immunotherapy : CII最新文献

{"title":"Novel recombinant protein PK5-Gal-3C enhances the anti-tumor activity of T cells via binding with TRPV2.","authors":"Guopeng Zhang, Wei Zhang, Xiaohuan Wei, Zhenyu Wang, Feitong Wang, Shishuo Sun, Haiheng Xu, Xiangye Liu, Qing Zhang, Xiaoge Gao","doi":"10.1007/s00262-026-04401-3","DOIUrl":"https://doi.org/10.1007/s00262-026-04401-3","url":null,"abstract":"<p><p>Investigating strategies to enhance T cell effector function can improve the adoptive immune responses to tumors and complement existing tumor immunotherapies. Here, we present a novel artificially designed recombinant protein, PK5-Gal-3C, which is composed of the fifth kringle domain of plasminogen (PK5) and the C-terminal carbohydrate-recognition domain of galectin-3 (Gal-3C). This protein exhibited potent anti-tumor activity by significantly enhancing T cell effector function. Specifically, PK5-Gal-3C directly activated T cells by binding to glycosylated TRPV2 via Gal-3C, a thermosensitive calcium-permeable cation channel, thereby promoting the influx of calcium ions to enhance T cells cytotoxicity via the activation of c-Jun. Correspondingly, inhibition of TRPV2 or c-Jun impaired the cytotoxicity of T cell mediated by PK5-Gal-3C. Additionally, PK5-Gal-3C demonstrated significant anti-tumor activity by enhancing T cell tumor infiltration and cytotoxicity in a mouse model, as well as improving the anti-tumor efficacy of CAR-T cells in solid tumors. In summary, PK5-Gal-3C is a safe and potent anti-tumor agent with promising potential for T cell-mediated cancer immunotherapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-elemene enhances the efficacy of PD-L1 inhibitor in lung cancer by reprogramming tumor-associated macrophages to M1 phenotype via suppressing FLT1/PI3K/AKT signaling.","authors":"Jianmin Wang, Yongxin Yu, Fenglin Lin, Hang Wang, Weiqi Nian","doi":"10.1007/s00262-026-04386-z","DOIUrl":"https://doi.org/10.1007/s00262-026-04386-z","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI), epitomized by PD-1/PD-L1 antibodies, have ushered in a new era in lung cancer treatment. However, ICI monotherapy is only applicable to a small subset of patients with high PD-L1 expression, while most patients with low expression require combination therapies. In this study, we found that β-elemene promotes M1 polarization of tumor-associated macrophages (TAMs) and enhances the efficacy of PD-L1 antibody (aPD-L1) in C57BL/6 mice. RNA sequencing and surface plasmon resonance revealed that β-elemene directly binds to FLT1 and inhibits the PI3K/AKT/FOXO1 signaling pathway, thereby mediating TAMs M1 polarization. Using Flt1 knockout mice, we further validated the critical role of Flt1 in TAMs polarization and confirmed that M1 polarization synergizes with aPD-L1 treatment. Furthermore, co-immunoprecipitation showed that the FLT1 intracellular domain binds to and phosphorylates the p85α subunit, triggering downstream signaling cascades. These findings elucidate the synergistic mechanism between β-elemene and aPD-L1. Moreover, given the clinical availability of both agents, they provide a strong rationale for further clinical evaluation of this combination therapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"αTrop2/αCD3 bispecific protein engager-armed T cells (BATs) exhibit potent antitumor activity against nasopharyngeal carcinoma.","authors":"Kwanpirom Suwanchiwasiri, Chalermchai Somboonpatarakun, Nan Chaiyariti, Utid Suriya, Surang Chankhamhaengdecha, Pa-Thai Yenchitsomanus, Tavan Janvilisri, Mutita Junking","doi":"10.1007/s00262-026-04406-y","DOIUrl":"https://doi.org/10.1007/s00262-026-04406-y","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) remains a highly aggressive malignancy with poor outcomes in advanced and recurrent disease. Although immune checkpoint inhibitors combined with chemotherapy improve survival, many patients still experience relapse or disease progression. Here, we developed a non-genetically modified cellular immunotherapy based on αTrop2/αCD3 bispecific protein engager-armed T cells (αTrop2/αCD3-BATs), targeting Trop2, which is highly expressed in NPC and minimally expressed in normal tissues. Molecular dynamics simulations supported stable dual binding of the BiPE to Trop2 and CD3ε, consistent with effective immune synapse formation. Functionally, αTrop2/αCD3-BATs exhibited potent, antigen-dependent cytotoxicity against Trop2-positive NPC cell lines (TW01, HK1, and CNE1) in both two-dimensional co-culture and three-dimensional spheroid models while sparing Trop2-negative cells. Target engagement induced robust T cell activation and proliferation, accompanied by increased expression of effector molecules such as FasL and elevated secretion of cytolytic mediators (perforin, granzymes, and granulysin) and pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). Collectively, these findings demonstrate that αTrop2/αCD3-BATs mediate potent and selective antitumor activity and support their further preclinical development as an MHC-independent cellular immunotherapy for Trop2-positive NPC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Thymic epithelial tumors at the crossroads of immunity, autoimmunity, and immunotherapy.","authors":"Kübra Canaslan, Fatemeh Moeini Nia, Maria Baez, Hassan Abolhassani, Natalie Ridge, Maroun Bou Zerdan, Jennifer Marks, Hussain Rangoonwala, Behnaz Jahanbin, Amir Hossein Emami, Katie O'Reilly, Yesim Gökmen-Polar, Sunil S Badve, Chunwei Xu, Yue Hao, Aparna Sharma, Swasthik Upadhya, Francoise Galateau Salle, Kelsey Pan, Badi El Osta, Dong M Shin, Fatemeh Ardeshir-Larijani","doi":"10.1007/s00262-026-04407-x","DOIUrl":"10.1007/s00262-026-04407-x","url":null,"abstract":"","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13149698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848965","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":"Rosuvastatin enhances the efficacy of venetoclax-azacitidine in older acute myeloid leukemia patients via reducing T-cell exhaustion.","authors":"Yuanmei Zhai, Yehua Yu, Renjun Bao, Jiajia Liu, Jianguo Fang, Wei Lu, Difan Zhang, Hezhou Guo, Yonghua Yao, Jun Shi","doi":"10.1007/s00262-026-04397-w","DOIUrl":"https://doi.org/10.1007/s00262-026-04397-w","url":null,"abstract":"<p><p>Venetoclax plus hypomethylating agents (HMAs) is a standard therapy for older or unfit patients with acute myeloid leukemia (AML); however, some patients exhibit suboptimal responses, potentially associated with T-cell exhaustion. Our preclinical findings that statins enhance HMA efficacy by boosting anti-tumor T-cell responses prompted us to translate this strategy to the clinic. A multicenter phase II clinical trial (ChiCTR 2500111931) was conducted to evaluate the efficacy and safety of adding rosuvastatin to venetoclax and azacitidine (venetoclax-azacitidine) in older/unfit AML patients. After induction therapy with this triple combination, the cohort achieved a complete response (CR) rate of 55.5% and a composite complete remission (CRc) rate of 72.2%. Among patients who achieved CRc, 84.6% attained measurable residual disease (MRD) < 10^-3. With a median follow-up of 10 months, the median overall survival (OS) and relapse-free survival (RFS) were 18 and 14 months, respectively. Although no significant changes in lipid profiles were observed, multiparametric flow cytometry revealed significant reductions in PD-1⁺CD4⁺ T cells (p = 0.0137) and PD-1⁺CD8⁺ T cells (p = 0.0277) after therapy. In vitro experiments revealed that the addition of rosuvastatin diminished both early (PD-1⁺TIM-3⁻) and terminally (PD-1⁺TIM-3⁺) exhausted T cells, suggesting it prevents the development of T-cell exhaustion induced by venetoclax-azacitidine. Furthermore, functional assays confirmed that rosuvastatin addition significantly enhanced T cell cytotoxicity against leukemia cells. Collectively, our findings suggest that adding rosuvastatin to venetoclax-azacitidine shows preliminary clinical activity and acceptable safety, possibly by reducing T-cell exhaustion, thus supporting further study of this triple regimen in older/unfit AML patients.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849014","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":"Artificial intelligence-powered H&E-based quantification of spatial tumor-infiltrating lymphocyte distribution identifies prognostic immune niches in colorectal cancer.","authors":"Hyun-Hee Koh, Seungeun Lee, Chiyoon Oum, Sanghoon Song, Soo Ick Cho, Sérgio Pereira, Chang Ho Ahn, Jun Yong Kim, Milim Kim, Minsun Jung","doi":"10.1007/s00262-026-04409-9","DOIUrl":"https://doi.org/10.1007/s00262-026-04409-9","url":null,"abstract":"<p><strong>Purpose: </strong>The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) is well established; however, existing approaches inadequately capture their spatial distribution. We investigated the prognostic implications of TIL spatial distribution in CRC using an artificial intelligence (AI)-based method.</p><p><strong>Methods: </strong>A total of 202 patients with stage II-III CRC were included. TIL densities in intratumoral (iTIL) and stromal (sTIL) regions were quantified using AI-based analysis of hematoxylin and eosin (H&E)-stained images. Based on proximity to the tumor-stromal border (TSB), TILs were subclassified into core iTIL, bounding iTIL, bounding sTIL, and outermost sTIL. Immunoscore was calculated from CD3⁺ and CD8⁺ T-cell densities in the tumor center and invasive margin.</p><p><strong>Results: </strong>Correlations between AI-based and pathologist assessments (iTIL: r = 0.57; sTIL: r = 0.70) were comparable to inter-pathologist correlations (iTIL: r = 0.47; sTIL: r = 0.70). In univariate Cox regression analysis, bounding iTIL, bounding sTIL, and outermost sTIL were significantly associated with recurrence-free survival (RFS), whereas core iTIL was not. Composite TIL and TSB scores were developed by incorporating the prognostically significant regions. In multivariable analysis, the TIL score (p = 0.001), TSB score (p < 0.001), and Immunoscore (p < 0.001) independently predicted RFS. In microsatellite instability-high tumors, only the TSB score remained prognostically significant.</p><p><strong>Conclusion: </strong>AI-powered spatial analysis of TILs, particularly the TSB score, demonstrated prognostic performance comparable to conventional Immunoscore, thereby supporting the value of spatial immune profiling and AI-driven analysis of H&E-stained slides for improved risk stratification in CRC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848984","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":"Dual-modality imaging enables longitudinal biodistribution profiling of intracerebroventricular CAR-T therapy in orthotopic glioma.","authors":"Chunzhao Li, Peng Zhang, Xiaobin Zhao, Rui Feng, Na Xian, Gangxiong Huang, Wenju Jiang, Zhenhua Hu, Yang Zhang, Nan Ji","doi":"10.1007/s00262-026-04403-1","DOIUrl":"10.1007/s00262-026-04403-1","url":null,"abstract":"<p><p>Locoregional CAR-T delivery is increasingly explored for glioblastoma to improve intracranial tumor exposure; however, organ-level biodistribution kinetics after intracranial administration remain poorly quantified in vivo, limiting route-informed optimization and preclinical risk assessment. Here, we report a dual-modality cell labeling and tracking strategy based on indocyanine green-conjugated iron nanoparticles (ICG-NPs) for in vivo assessment of B7-H3-targeting CAR-T cell (TX103) biodistribution using second near-infrared window (NIR-II) fluorescence imaging and magnetic resonance imaging (MRI). Using a heparin-protamine-assisted protocol, TX103 cells were labeled with high efficiency (83.1%) without detectable changes in viability, CAR expression, immunophenotype (including activation/exhaustion marker profile and CXCR3 expression), or cytotoxic function. In vitro imaging demonstrated a linear correlation between NIR-II fluorescence intensity and labeled cell numbers (R² = 0.973, p < 0.001), while MRI provided complementary anatomical context at higher cell densities. In an orthotopic glioma mouse model, longitudinal MRI and NIR-II imaging captured route-dependent differences in tumor-associated localization and whole-body biodistribution following intracerebroventricular and intravenous administration. Furthermore, organ-level NIR-II exposure showed a positive association with CD3⁺ T-cell density across organs (R² = 0.552, p < 0.001), supported by multi-organ pathological validation. Collectively, we establish a biocompatible dual-modality workflow that links intracranial anatomical localization with longitudinal whole-body biodistribution readouts for preclinical CAR-T tracking in solid tumor models.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 5","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825929","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":"Evaluation of the predictive and prognostic potential of blood immune cell profiles in metastatic cancer patients treated with immune checkpoint inhibitors.","authors":"Veera Nurmela, Anna-Mari Schroderus, Satu Tiainen, Outi Kuittinen, Olli Tenhunen, Anna Jokimäki, Sanna Suoranta, Sanna Pasonen-Seppänen, Tero Sievänen, Tuure Kinnunen, Aino Rönkä","doi":"10.1007/s00262-026-04404-0","DOIUrl":"10.1007/s00262-026-04404-0","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have transformed the treatment of metastatic malignancies, yet only 20-40% of unselected patients benefit. Peripheral blood could offer a minimally invasive and dynamic source for predictive biomarkers of ICI therapy.This study evaluated circulating immune cell frequencies and phenotypes before and during ICI therapy to identify tumor-agnostic blood-based biomarkers. We analyzed routine blood immune cell counts in a retrospective cohort of 202 patients treated with ICIs. Next, we investigated the findings in a prospectively collected cohort of 45 patients using multiparametric flow cytometry for characterization of immune cell subsets. We considered early radiological response, progression-free survival (PFS), and overall survival (OS) as clinical outcomes.Higher pre-treatment monocyte and lower lymphocyte counts were consistently associated with inferior PFS and OS but not with early radiological response in the retrospective cohort. In the prospective cohort, detailed immunophenotyping identified elevated pre-treatment frequencies of intermediate (CD14⁺CD16⁺) monocytes as a marker of poorer PFS and OS. Within lymphocyte subsets, higher T cell frequencies were associated with better OS, and a higher pre-treatment frequency of CD226-expressing CD8⁺ memory T cells with better ICI response. ICI therapy induced increase in TIGIT⁺CD8⁺ and CD4⁺ memory T cell subsets, regardless of treatment response.In conclusion, elevated pre-treatment levels of blood monocytes, together with decreased levels lymphocytes, were associated with poor survival of ICI-treated patients. Although detailed immunophenotyping of pre-treatment blood immune cell populations showed limited predictive utility, specific subpopulations, such as intermediate monocytes and CD226⁺CD8⁺ memory T cells, may harbor potential as prognostic/predictive indicators.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 5","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825963","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":"Integrating single-cell and bulk transcriptomes to reveal prognostic and immunological features of ecDNA-related genes in osteosarcoma.","authors":"Jinyan Feng, Jianchao Liu, Houzhi Yang, Yiqin Li, Yao Xu, Xiuxin Han, Chao Zhang, Guowen Wang","doi":"10.1007/s00262-026-04383-2","DOIUrl":"10.1007/s00262-026-04383-2","url":null,"abstract":"<p><strong>Background: </strong>The role of extrachromosomal DNA (ecDNA)-related genes in osteosarcoma remains largely unexplored. The aim of this study is to investigate the association between ecDNA-related genes and prognosis and tumor microenvironment (TME) in osteosarcoma.</p><p><strong>Methods: </strong>Differential gene expression analysis of GEO datasets was conducted to identify ecDNA-related genes in osteosarcoma. Based on bulk RNA-seq data, a novel ecDNA-related Gene Prognostic Score Model (EGPSM) was developed using an integrated framework of 101 machine learning algorithms, which was validated in training, testing, and external cohorts. The associations between risk scores, prognosis, and TME characteristics were comprehensively evaluated. Single-cell RNA sequencing (scRNA-seq) data were further analyzed to elucidate the relationship between EGPSM, pro-tumor behaviors, and immune modulation in osteosarcoma, as well as to identify key prognostic genes involved in tumor progression. Lastly, we conducted in vitro and in vivo assays to characterize the biological roles of MTDH and to elucidate its regulatory effects on CD8⁺ T cell function.</p><p><strong>Results: </strong>A robust EGPSM was constructed, demonstrating superior predictive accuracy with a maximum C-index of 0.803. High-risk patients exhibited poorer survival, higher metastatic potential, and an \"immune-cold\" TME characterized by diminished CD8⁺ T/NK cell infiltration and impaired effector functions. Single-cell analysis confirmed the enrichment of malignant cells and depletion of T/NK populations with lower effector scores in the high-risk group. MTDH was identified as a key driver; functional assays showed it promotes proliferation and invasion while inhibiting apoptosis. Notably, MTDH knockdown potentiated CD8⁺ T-cell cytotoxicity by increasing the levels of granzyme B, IFN-γ, and perforin.</p><p><strong>Conclusion: </strong>The newly developed EGPSM represents an effective tool for prognostic assessment and therapeutic stratification in osteosarcoma. MTDH may serve as a promising prognostic biomarker and therapeutic target.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 5","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794950","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":"Immune classification of advanced melanoma identifies non-responders to anti-PD1 therapy.","authors":"Angelo Gámez-Pozo, Lucía Trilla-Fuertes, Fernando Becerril-Gómez, Pedro Lalanda-Delgado, Virtudes Soriano, Fernando Garicano Goldaraz, M José Lecumberri, María Rodríguez de la Borbolla, Margarita Majem, Elisabeth Pérez-Ruiz, María González-Cao, Juana Oramas, Rocío López-Vacas, Alejandra Magdaleno, Joaquín Fra, Alfonso Martín-Carnicero, Mónica Corral, Teresa Puértolas, Ricardo Ramos-Ruiz, Enrique Espinosa, Juan Ángel Fresno Vara","doi":"10.1007/s00262-026-04392-1","DOIUrl":"10.1007/s00262-026-04392-1","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy based on anti-PD1 inhibitors has significantly improved survival in advanced melanoma. However, a significant proportion of patients do not benefit, and predicting response to immunotherapy remains an area of unmet need. Our group previously defined an immune signature able to predict response to anti-PD1 inhibitors in this scenario.</p><p><strong>Methods: </strong>In this study, we analyzed two cohorts of patients with advanced melanoma treated with anti-PD1 inhibitors: the GEM cohort, previously used to validate our immune signature, and Campbell's cohort, which contains data about different immunotherapy schemes. Using the 107 genes that compose our immune signature and consensus clustering, samples were classified as immune-low or immune-high. Then, CIBERSORTx and Ecotyper were used to estimate the proportion of each immune cell type and carcinoma ecotypes in both cohorts.</p><p><strong>Results: </strong>We confirmed that the immune-low group includes mostly patients who do not response to anti-PD1 inhibitors. We also studied the distribution of carcinoma ecotypes in the immune-high and immune-low groups defined by our immune classification. Ecotypes CE9 and CE10 clustered in the immune-high group, with good response to treatment. The use of combination immunotherapy improved response rate both in immune-low and immune-high tumors. The immune-high group contained a higher number of CD8 T cells, B memory cells and T follicular helper cells.</p><p><strong>Conclusions: </strong>Our immune-based classification defines an immune-low group of tumors with poor response to anti-PD1 inhibitors. This immune classification is related to carcinoma ecotypes. Finally, a use of a combo scheme improves the rates of response both in immune-high and low groups but in the case of immune-low tumors, our results suggests that a combo treatment approach could be an adequate strategy and should be further explored in these patients. Altogether, our results support the utility of our immune signature in the prediction of response to anti-PD1 inhibitors in advanced melanoma.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 5","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794793","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}