Cancer immunology, immunotherapy : CII最新文献

{"title":"Gut modulation to regulate NF-κB in colorectal and gastric cancer therapy and inflammation.","authors":"Rowan Kearns","doi":"10.1007/s00262-025-04118-9","DOIUrl":"10.1007/s00262-025-04118-9","url":null,"abstract":"<p><p>The nuclear factor-kappa B (NF-κB) pathway plays a pivotal role in cancer progression, immune regulation, and inflammation. Aberrant activation of this pathway, often driven by gut microbiota dysbiosis, contributes to tumorigenesis, therapy resistance, and chronic inflammation. Emerging evidence highlights the bidirectional interaction between gut microbiota and NF-κB signalling, suggesting that microbiota modulation may enhance cancer treatment efficacy and reduce treatment-induced inflammation. This review explores the mechanistic underpinnings of gut microbiota-mediated NF-κB regulation, focusing on microbial metabolites such as short-chain fatty acids (SCFAs) and microbial-associated molecular patterns, including lipopolysaccharides (LPS). It examines how conventional cancer treatments, chemotherapy, radiotherapy, and immune checkpoint inhibitors, exacerbate dysbiosis and NF-κB-driven inflammation, further complicating treatment outcomes. Additionally, this review evaluates the therapeutic potential of gut-targeted interventions, including probiotics, prebiotics, faecal microbiota transplantation (FMT), and dietary modifications, in restoring microbial homeostasis and modulating NF-κB signalling. Despite promising findings, challenges remain regarding the clinical translation of microbiota-based therapies, including the need for standardised microbiota profiling, regulatory frameworks, and long-term safety assessments. Advances in metagenomics and metabolomics are proposed as essential tools to personalise gut-targeted interventions and optimise cancer treatment strategies. Integrating gut modulation into oncology represents a paradigm shift, offering a holistic, patient-centric approach to cancer therapy. However, further research is required to validate these strategies and ensure their efficacy in clinical applications.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"264"},"PeriodicalIF":0.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621648","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":"Correlation between T cell immunity and the duration of EGFR-TKI resistance acquisition in patients harboring EGFR mutations.","authors":"Atsuto Mouri, Kyoichi Kaira, Ou Yamaguchi, Ayako Shiono, Yu Miura, Kosuke Hashimoto, Satoshi Yamasaki, Fuyumi Nishihara, Hisao Imai, Kunihiko Kobayashi, Hiroshi Kagamu","doi":"10.1007/s00262-025-04113-0","DOIUrl":"10.1007/s00262-025-04113-0","url":null,"abstract":"<p><strong>Background: </strong>Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) control lung cancer in patients with EGFR mutations, but resistance develops over time. Patients with high levels of genetic mutations rapidly acquire EGFR-TKI resistance. T cell immunity recognizes gene mutation products as neoantigens that effectively suppress mutation levels by eliminating clones with more mutations; this process is known as cancer immune editing. Therefore, EGFR-TKI-resistant clones may be less likely to form in cases with active antitumor T cell immune responses. However, the relationship between EGFR-TKI resistance and antitumor T cell response in patients with EGFR mutation remains unclear. To determine the relationship between the duration of EGFR-TKI resistance acquisition and antitumor T cell immunity, and the effect of EGFR-TKIs on T cell immunity.</p><p><strong>Methods: </strong>This prospective observational study enrolled 43 patients who received osimertinib. Blood samples were collected prior to and following 4 weeks of EGFR-TKI administration.</p><p><strong>Results: </strong>The median PFS and OS for the 37 patients were 24.8 and 32.9 months, respectively. Patients with higher CXCR3⁺CCR4^-CCR6⁺CD4⁺ T cell levels exhibited significantly enhanced PFS (p = 0.002) and OS (p = 0.0006). Other T cell subsets (Th1, Th2, Th17, and CD8⁺) exhibited no significant correlation with PFS. The percentage of CXCR3⁺CCR4^-CCR6⁺CD4⁺ T cells was significantly reduced with tumor volume reduction (p < 0.0001).</p><p><strong>Conclusions: </strong>T cell immunity affects the time required to acquire resistance after EGFR-TKI treatment. Pretreatment CXCR3⁺CCR4^-CCR6⁺CD4⁺ T cell cluster was significantly associated with PFS after osimertinib treatment, likely predicting osimertinib efficacy. Antitumor T cell immunity may be crucial for preventing the acquisition of EGFR-TKI resistance.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"265"},"PeriodicalIF":0.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621647","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":"Clinical outcomes following PD-1 inhibitor elective discontinuation in cutaneous squamous cell carcinoma: exploring treatment de-escalation.","authors":"Itamar Averbuch, Nofar Edri, Nethanel Asher, Gal Markel, Daniel Hendler, Hadas Ditzian Kugler, Eyal Yosefof, Noga Kurman","doi":"10.1007/s00262-025-04115-y","DOIUrl":"10.1007/s00262-025-04115-y","url":null,"abstract":"<p><strong>Background: </strong>Non-melanoma skin cancers (NMSC) are the most common malignancies worldwide. While early-stage lesions can be definitively treated with local therapies, advanced stage cutaneous squamous cell carcinoma (cSCC) often requires systemic treatments such as PD-1 inhibitors. These treatments may be administered for prolonged durations; this practice may lead to an unnecessary physical and financial toxicity. The purpose of this study was to evaluate the patterns of disease progression after anti-PD-1 therapy discontinuation in this group of patients.</p><p><strong>Methods: </strong>This retrospective cohort study included patients diagnosed with advanced cSCC and treated with either cemiplimab or pembrolizumab from 2019 to 2024 at a single university-affiliated tertiary medical center.</p><p><strong>Results: </strong>The cohort included 131 patients, with a 73% overall response rate. Among the 86 patients with either partial or complete response as the best response included in the final analysis, 40 (47%) patients had a treatment break for at least 3 months, and 46 (53%) continued without discontinuation to a maximal duration of 2 years. After a median follow-up of 29.9 months, 24 (60%) patients in the break group remained progression-free, systemic treatment-free, and alive throughout the follow-up. Four patients (10%) experienced disease progression. Among these, the best overall response was PR in three patients and CR in one patient. Nine (22.5%) patients died due to non-oncological reasons, two (5%) patients died from an unknown cause, and one (2.5%) due to treatment toxicity. The percentage of patients achieving CR was statistically significantly higher in the break group compared to the no-break group.</p><p><strong>Conclusions: </strong>Our findings advocate for a more tailored approach to the duration of PD-1 inhibitor therapy in cSCC, potentially reducing burdens of overtreatment. Future studies regarding establishing robust predictors for safe treatment discontinuation are required to enhance decision-making in clinical practice.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"260"},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568304","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":"Impact of stratifin/14-3-3σ on survival and interstitial lung disease in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.","authors":"Daiki Murata, Koichi Azuma, Kenta Murotani, Yoshiaki Zaizen, Tomoaki Hoshino","doi":"10.1007/s00262-025-04093-1","DOIUrl":"10.1007/s00262-025-04093-1","url":null,"abstract":"<p><strong>Background: </strong>Stratifin/14-3-3σ (SFN) is a new diagnostic biomarker of interstitial lung disease (ILD) with a diffuse alveolar damage (DAD) pattern as well as a predictor of resistance to anticancer therapy. Despite the potential clinical benefit of SFN, its impact on therapeutic efficacy of immune checkpoint inhibitors (ICIs) and ICI-induced interstitial lung disease (ICI-ILD) in patients with non-small cell lung cancer (NSCLC) receiving cancer immunotherapy is unknown.</p><p><strong>Methods: </strong>Plasma samples were collected from patients with NSCLC at ICI initiation and 6 weeks later. The relationship between SFN levels and therapeutic efficacy of ICIs and development of ICI-ILD was analyzed.</p><p><strong>Results: </strong>Pre-SFN levels were measured for 165 patients and post- and delta-SFN levels were measured for 113 patients. Of the patients with pre-SFN values, 25 developed ICI-ILD and 10 exhibited a DAD pattern. Among patients with post- and delta-SFN values, 15 developed ICI-ILD, and 6 had a DAD pattern. Pre- and post-SFN levels were not associated with ICI therapeutic efficacy or ICI-ILD. Meanwhile, delta-SFN, representing the change in SFN values between ICI initiation and at the 6-week point, was associated with progression-free survival, overall survival, disease control rate, and ICI-ILD image patterns.</p><p><strong>Conclusion: </strong>SFN levels in plasma were associated with therapeutic efficacy and ICI-ILD pattern in patients with NSCLC receiving cancer immunotherapy. SFN can be a diagnostic biomarker for ICI-ILD with DAD patterns as well as a prognostic biomarker for cancer immunotherapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"261"},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568306","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":"Favorable impact of zanubrutinib combined with R-CHOP regimen in MYD88-mutated new-diagnosed diffuse large B-cell lymphoma: a retrospective study with propensity score-matched analysis.","authors":"Xiubin Xiao, Shunzong Yuan, Xilin Chen, Xia Liu, Ruiqing Zhao, Shihua Zhao, Yun Lu, Yi Ma, Junli Chen, Yueqi Wang, Nana Cheng, Hua Yin, Honghao Gao, Pan Feng, Wenrong Huang","doi":"10.1007/s00262-025-04090-4","DOIUrl":"10.1007/s00262-025-04090-4","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with MYD88 mutations associated with poor outcomes. Enhancing standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy with targeted agents such as zanubrutinib, a selective Bruton tyrosine kinase inhibitor, may improve patient prognosis. This retrospective study evaluated patients with MYD88-mutated DLBCL treated with zanubrutinib plus R-CHOP (ZR-CHOP). The ZR-CHOP group (n = 20) was compared with a propensity score-matched control group (n = 40) of patients without MYD88 mutation who received standard R-CHOP. Key outcomes included complete response rate (CRR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Univariate logistic regression analyzed prognostic factors, and safety was assessed by comparing adverse events between groups. The ZR-CHOP group had a similar CRR of 75.0% compared to 67.5% in the control group and an ORR of 90.0% versus 97.5%. With a median follow-up of 26.5 months (range: 1-41), PFS and OS were analyzed. At 36 months, PFS was 61.9% in the ZR-CHOP group versus 63.8% in the control, while OS was 77.5% versus 76.7%. Among patients with MYD88/CD79B double mutations, the CRR was 90.0%. Elevated lactate dehydrogenase levels were linked to a lower likelihood of achieving a complete response. The most common treatment-related adverse events were infections (50%) and bleeding (15%) in the ZR-CHOP group. ZR-CHOP may improve outcomes in MYD88-mutated DLBCL, particularly in patients with MYD88/CD79B double mutations. Although further studies are needed, zanubrutinib shows promise as a targeted therapy in this population.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"259"},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568305","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":"Divergent therapeutic and prognostic impacts of immunogenic features in undifferentiated pleomorphic sarcoma and myxofibrosarcoma.","authors":"Siddh van Oost, Debora M Meijer, Zeynep B Erdem, Marieke E IJsselsteijn, Jessica Roelands, Suk Wai Lam, Melissa S Boejharat, Brendy E W M van den Akker, Ruud van der Breggen, Inge H Briare-de Bruijn, Lukas J A C Hawinkels, Anouk A Kruiswijk, Manon van der Ploeg, Pauline M Wijers-Koster, Rick L Haas, Michiel A J van den Sande, Noel F C C de Miranda, Judith V M G Bovee","doi":"10.1007/s00262-025-04123-y","DOIUrl":"10.1007/s00262-025-04123-y","url":null,"abstract":"<p><p>Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are genetically complex soft tissue sarcomas with distinct morphological features. Treatment typically involves surgery, often combined with neoadjuvant chemo- or radiotherapy. To better understand the immunobiology of these sarcomas and its associations with treatment response and prognosis, we performed transcriptomic and immunophenotypic profiling. RNA sequencing was performed on 13 UPS and 10 MFS, and immunological profiles were compared with soft tissue sarcoma data from The Cancer Genome Atlas (n = 206 including 44 UPS and 17 MFS). Immune contextures were further evaluated in 14 UPS and 15 MFS using imaging mass cytometry. Characterization of T cell and macrophage infiltration in tumors was further assessed in 23 UPS and 22 MFS through multispectral immunofluorescence and immunohistochemical analysis. UPS and MFS demonstrated immunogenic features compared to other soft tissue sarcomas, with subsets of UPS and MFS demonstrating high T cell infiltration, while UPS demonstrated a higher infiltration by myeloid cells as compared to MFS. Prognostically, T cells and CD68⁺CD163⁺ macrophages were associated with metastasis-free survival in UPS but not in MFS. Notably, in UPS, neoadjuvant radiotherapy appeared to induce cytotoxic T cell infiltration and depletion of myeloid cells, whereas these effects were not observed in MFS. These findings highlight important differences in the immunobiology of UPS and MFS with therapeutic and prognostic implications. These differences should be taken into account given the growing availability of immunotherapeutic options for treating patients with soft tissue sarcomas.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"258"},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546786","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":"TCR-based cellular immunotherapy for hepatocellular carcinoma: advances, challenges, and prospects.","authors":"Wanting Zeng, Wei Zhu, Guosheng Yuan, Jinzhang Chen, Zhanhui Wang, Jinlin Hou, De-Ke Jiang","doi":"10.1007/s00262-025-04122-z","DOIUrl":"10.1007/s00262-025-04122-z","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors globally. However, current frontline treatment modalities fail to achieve satisfactory therapeutic outcomes. In recent years, T-cell receptor (TCR)-T therapy has garnered increasing attention as a promising therapeutic approach. This review provides an overview of the epidemiology of HCC, evaluates the efficacy of current first-line treatment options, and introduces adoptive cellular therapies (ACTs), with a specific focus on TCR-T therapy. Notably, we categorize existing TCR-T research targeting different antigens for the treatment of HCC, covering both published literature and registered clinical trials. Furthermore, we discuss the limitations of current TCR-T research and applications, while offering insights into future research directions and development prospects. In summary, this review comprehensively examines the research progress on TCR-T therapy for HCC from the perspective of antigen targeting. Although several challenges remain to be addressed, we believe that TCR-T therapy represents a promising approach for the treatment of HCC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"257"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546787","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":"Salvianic acid A enhances anti-PD-1 therapy by promoting HEV-mediated stem-like CD8 T cells infiltration in TNBC.","authors":"Xiaoming Ding, Gai Liang, Yan Luo, Xiaomei Zhou, Qu Zhang, Bo Luo","doi":"10.1007/s00262-025-04116-x","DOIUrl":"10.1007/s00262-025-04116-x","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to investigate the potential of Salvianic acid A (SAA) to enhance the efficacy of anti-PD-1 immunotherapy in triple-negative breast cancer (TNBC), with a focus on elucidating the mechanisms.</p><p><strong>Methods: </strong>To explore the effects of SAA on anti-PD-1 therapy efficacy, we established a mouse tumor model using 4T1 breast cancer cells and treated groups with SAA, anti-PD-1 (αPD-1), or their combination. Tumor growth, weight, and survival were monitored. A melanoma mouse model using B16 melanoma cells was also used to validate the efficacy of SAA enhanced immunotherapy. Tumor tissues were analyzed histologically and by flow cytometry to assess immune cell infiltration and function. The expression of immune markers and cytokines was evaluated using immunohistochemistry, Western blot, and quantitative RT-PCR. In vitro experiments were conducted on 4T1, MDA-MB-231, and MDA-MB-453 breast cancer cell lines, as well as CD8 T cells and endothelial cells, to investigate the direct effects of SAA on cell viability, activation, and phenotype maintenance. Additionally, the impact of SAA on high endothelial venules (HEVs) was assessed using immunofluorescence and flow cytometry.</p><p><strong>Results: </strong>The combination of SAA and anti-PD-1 therapy significantly inhibited tumor growth and prolonged survival in the 4T1 mouse model and B16 mouse model respectively, compared to controls (P < 0.001). Tumor volumes and weights were consistently lower in the combination group, with no significant weight loss or toxicity observed. Histological analysis revealed increased stromal content and reduced tumor cell density in the SAA + αPD-1 group, indicating enhanced immune cell infiltration and tumor cell death. Flow cytometry showed that SAA significantly increased the infiltration of CD8 T cells and stem-like CD8 T cells (TCF1 and SLAMF6) into the tumor microenvironment when combined with αPD-1 (P < 0.001). The combination also enhanced the expression of IFN-γ and Ki-67 in CD8 T cells, indicating improved functional capacity. Additionally, SAA promoted the formation of HEVs in tumor tissues, as evidenced by increased CD31 and MECA-79 staining (P < 0.001). In vitro, SAA did not directly inhibit breast cancer cell viability or activate CD8 T cells but maintained the high endothelial phenotype in endothelial cells by upregulating key markers such as ACKR1 and CDH5. These findings demonstrate that SAA enhances anti-PD-1 efficacy by modulating the tumor immune microenvironment and promoting HEV formation, without direct cytotoxic effects on cancer cells or immune cells.</p><p><strong>Conclusion: </strong>SAA significantly enhances the efficacy of anti-PD-1 therapy by promoting HEV-mediated stem-like CD8 T cells infiltration in TNBC. The combination of SAA and αPD-1 represents a promising therapeutic strategy that warrants further exploration in preclinical and clinical settings.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"256"},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532731","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":"Diversity of mast cell subpopulations in the tumor microenvironment of colorectal cancer and their prognostic implications.","authors":"Tianyu Qiao, Chao Ding, Songtao Yu, Wenyang Li, Yonghou Zhao, Guiyu Wang","doi":"10.1007/s00262-025-04119-8","DOIUrl":"10.1007/s00262-025-04119-8","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is one of the most common and deadly malignancies worldwide, with a particularly low 5-year survival rate in advanced patients. Immune cells in the tumor microenvironment, especially mast cells, play crucial roles in tumor initiation and progression. However, the dual role of mast cells in CRC remains poorly understood.</p><p><strong>Methods: </strong>In this study, we used single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing, and bioinformatics analyses to explore the heterogeneity of mast cell subpopulations in the CRC tumor microenvironment and their relationship with prognosis. We analyzed gene expression signatures associated with mast cell subpopulations derived from single-cell data of 40 CRC tumor samples and combined bulk RNA-seq data from HMU, GEO, and TCGA cohorts for prognostic prediction. Non-negative matrix factorization was used for clustering of mast cell subpopulations, followed by analysis of their specific gene markers, transcription factor activity, and biological pathways. Survival analysis and ROC curves were performed to assess their prognostic significance.</p><p><strong>Results: </strong>Mast cells in the CRC tumor microenvironment were classified into three distinct subpopulations, each with unique gene markers and functional pathways. Mast cell subpopulations 1 and 3 were highly associated with pro-tumor pathways, while mast cell subpopulation 2 primarily exhibited anti-tumor immune regulatory characteristics. High expression of mast cell subpopulations 1 and 3 was associated with poor survival prognosis, while high expression of subpopulation 2 was linked to a better survival outcome. Key marker genes such as DNAJB1, SEMA7A, and XCR1 were identified as potential prognostic factors, with high expression of DNAJB1 and SEMA7A being significantly associated with poor prognosis, while high expression of XCR1 was linked to a favorable prognosis.</p><p><strong>Conclusion: </strong>This study reveals the functional heterogeneity of mast cell subpopulations in the CRC tumor microenvironment and their differential roles in tumor progression. Identification of mast cell subpopulation-specific marker genes provides new molecular targets for clinical diagnosis, prognostic prediction, and personalized immunotherapy in CRC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"255"},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532730","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":"Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma.","authors":"Daniela Lorizio, Manuela Silginer, Julia Friesen, Alan L Epstein, Michael Weller, Patrick Roth","doi":"10.1007/s00262-025-04098-w","DOIUrl":"10.1007/s00262-025-04098-w","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment of glioblastoma limits the effectiveness of most immunotherapies. Transforming growth factor (TGF)-β signaling drives tumor progression and prevents effective T cell activity. Notably, both regulatory T cells (Tregs) and effector T cells within glioblastoma and other tumors express high levels of the immune checkpoint receptor, glucocorticoid-induced tumor necrosis factor receptor (GITR), which modulates T cell activation and function. Combining GITR agonism with TGF-β inhibition may therefore offer a compelling approach to restore anti-tumor immunity. We evaluated the combined effects of TGF-β inhibition and GITR modulation using two different GITR agonists in syngeneic mouse glioma models. GITR modulation enhanced T cell activation, as shown by increased cytokine secretion and effector T cell proliferation in vitro. Combining GITR modulation with TGF-β inhibition amplified these effects, resulting in significantly stronger immune cell-mediated tumor cell killing compared to single-agent treatments. Combination therapy improved survival of glioma-bearing mice, with a higher fraction of long-term survivors compared to monotherapy. Surviving mice resisted tumor re-challenge, indicating durable adaptive immunity. In summary, dual targeting of TGF-β and GITR pathways synergistically enhances anti-tumor immunity in glioblastoma. This novel combination strategy demonstrates clinical potential by addressing the limitations of existing immunotherapies and offering a promising approach for durable and effective glioblastoma treatment.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 8","pages":"254"},"PeriodicalIF":0.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532732","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}