Cancer immunology, immunotherapy : CII最新文献

{"title":"Integrative single-cell and multi-omics analysis of ZBTB21-mediated serine metabolism in colorectal cancer: from metabolic reprogramming to immune microenvironment modulation.","authors":"Yimei Jiang, Haiyan Huang, Haoran Feng, Kun Liu, Yiqing Shi, Zijia Song, Xi Cheng, Xiaopin Ji, Ren Zhao","doi":"10.1007/s00262-026-04427-7","DOIUrl":"10.1007/s00262-026-04427-7","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) exhibits pronounced biological diversity, a feature increasingly attributed to alterations in cellular metabolic reprograms. Serine metabolism supports nucleotide synthesis, redox balance, and epigenetic regulation via one-carbon metabolism, yet its role in shaping the tumor cellular interactions and immune landscape at single-cell level remains unclear.</p><p><strong>Methods: </strong>Single-cell transcriptomic profiles (GSE284449) were jointly analyzed with bulk expression datasets (GSE271719), together with Mendelian randomization (MR)-based inference, to dissect serine metabolism in CRC. High-serine-metabolism (HSM) cell populations were identified using scMetabolism, and robust marker genes were selected through Lasso, random forest, XGBoost, and SVM-RFE machine learning approaches. MR was applied to evaluate causal associations with CRC risk. Functional validation included IHC, qRT-PCR, western blot, and LC-MS metabolomics, while CellChat analysis characterized HSM cell interactions with immune and stromal cells.</p><p><strong>Results: </strong>ZBTB21 and TRPM2 were identified as core regulators of HSM cells, with ZBTB21 predominantly expressed in monocytes and pro-B cells. MR analysis suggested a potential inverse association between genetically predicted ZBTB21 expression and CRC risk, indicating that ZBTB21 may exert context-dependent effects at the population level. Cell-cell communication analysis suggested that HSM monocytes may interact with fibroblasts through signaling pathways including the MIF-SPP1 axis; however, these interactions are computationally inferred and require further experimental validation. Functional assays showed that ZBTB21 overexpression upregulated PHGDH and SHMT1, increased intracellular NADPH/NADP⁺ ratios, and influenced monocyte-related phenotypes. ZBTB21 levels were markedly increased in CRC samples relative to matched non-tumorous mucosal tissues.</p><p><strong>Conclusions: </strong>At single-cell resolution, ZBTB21 emerges as a metabolic regulator that strengthens serine biosynthesis and redox homeostasis. While integrative analyses suggest a potential link between ZBTB21-associated metabolic states and immune interactions, further experimental validation is required to establish causal relationships. This integrative framework connects genetic causality, metabolism, and immune interactions, providing mechanistic insights and potential strategies for metabolic-targeted therapies in CRC.</p><p><strong>Trial registration: </strong>Not applicable.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388478","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":"GLP-1 receptor agonists at immune checkpoint inhibitor initiation with immune-related and supportive-care outcomes in patients with cancer and overweight or obesity without diabetes: a target trial emulation.","authors":"Yu-Jung Lin, Pei-Yun Li, Shao-Chia Chen, Gideon Meyerowitz-Katz, Yu-Nan Huang, Pen-Hua Su","doi":"10.1007/s00262-026-04488-8","DOIUrl":"10.1007/s00262-026-04488-8","url":null,"abstract":"<p><strong>Aims: </strong>Sarcopenia, cachexia, and malnutrition are common in patients on immune checkpoint inhibitors (ICIs). GLP-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management in patients with obesity, including those with cancer. Whether GLP-1 RA use at ICI initiation relates to wasting-related outcomes in patients without diabetes is unknown. We examined whether GLP-1 RA supply at ICI start was linked to wasting-related diagnoses and acute-care use.</p><p><strong>Materials and methods: </strong>We used target-trial emulation with TriNetX US data. Adults with cancer and obesity/overweight starting an ICI were included. Baseline diabetes in the prior 12 months were excluded, with a 90-day GLP-1 RA washout. Exposure was a GLP-1 RA prescription or administration within a prespecified 30-day peri-initiation window before or after ICI initiation, versus none. Cohorts were 1:1 propensity score matched and followed up to 36 months; associations were estimated with intention-to-treat Cox models.</p><p><strong>Results: </strong>After matching, 1974 patients were analyzed (987 per group). Over 36 months, GLP-1 RA overlap was associated with fewer immune-related adverse events (HR 0.63, 95% CI 0.50-0.79); hospitalization (HR 0.67, 0.51-0.89), ICU (HR 0.69, 0.53-0.90), and emergency department visits (HR 0.68, 0.53-0.89) were also lower.</p><p><strong>Conclusions: </strong>GLP-1 RA add-on at ICI initiation was associated with fewer recorded wasting-related diagnoses and less acute-care use. The all-cause mortality reduction is exploratory, likely reflecting channeling bias rather than causation. These findings support prospective evaluation of GLP-1 RAs as supportive-care add-on therapy in ICI-treated patients with obesity.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388489","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":"Multidimensional analysis of tumour immune microenvironment in HCC: prognostic significance and implications for immunotherapy.","authors":"Jun Chen, Mingzhen Zhou, Wenyan Cao, Ziyan Zhou, Xintao He, Xiaohong Pu, Xiaojiao Hao, Sidong Chen, Yuchang Zhou, Jie Ma, Sihui Zhu, Shuting Huang, Jie Shen","doi":"10.1007/s00262-026-04485-x","DOIUrl":"10.1007/s00262-026-04485-x","url":null,"abstract":"<p><strong>Background: </strong>The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents the standard first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, most patients do not derive sustained clinical benefit. Emerging evidence has underscored a strong association between immunotherapy efficacy and the tumor immune microenvironment (TIME) in HCC. Accordingly, this study aimed to characterize the TIME and develop a potential approach for predicting patient survival.</p><p><strong>Methods: </strong>We analyzed a cohort of 78 patients with unresectable HCC who received ICIs combined with anti-angiogenic therapy. Four multiplex immunohistochemistry (mIHC) panels were designed to comprehensively evaluate tumor-infiltrating immune cells (TIICs). Digital pathology was applied to raw imaging data to extract TIME features, including positive rates and spatial distributions of TIICs. Machine learning algorithms were then used to construct predictive models based on TIME-associated signatures (TIS).</p><p><strong>Results: </strong>High positive rates of CD103⁺ and CD103⁺CD8⁺ T cells were associated with prolonged overall survival (OS). Conversely, a high positive rate of CD8⁺PD-L1⁺ T cells correlated with shorter progression-free survival (PFS). A greater abundance of CD8⁺ and CD103⁺ T cells in close proximity to tumor cells was also associated with longer OS. Multivariate Cox models incorporating these cell populations demonstrated that a lower TIS was significantly associated with longer OS and PFS.</p><p><strong>Conclusions: </strong>The composition and spatial distribution of immune cells critically shape the TIME in HCC and influence immunotherapy outcomes. TIS-based models show promise for predicting immunotherapy response in HCC patients, though they require further validation in larger prospective cohorts. These immune cell populations may serve as prognostic biomarkers and potential targets for personalized immunotherapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379480","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":"NKG2A-HLA-E and TIM3-galectin 9 pathways promote immune inhibition and represent therapeutic vulnerabilities in pancreatic ductal adenocarcinoma.","authors":"Yuanyu Lin, Wanhua Feng, Yan Li, Yisen Tang, Xiaomei Zhuang, Yingzi Huang, Juping Xie, Kai Liu, Youwen Fan, Yajun Tang, Dong Li, Ziming He, Yuxiong Qiu, Junzong Chen, Jie Xu, Zheng Yang, Linxiang Lan, Di Tang, Gang Deng, Guoying Zhou","doi":"10.1007/s00262-026-04479-9","DOIUrl":"10.1007/s00262-026-04479-9","url":null,"abstract":"<p><strong>Background: </strong>The roles of NKG2A-HLA-E and TIM3-galectin 9 immune checkpoint pathways in pancreatic ductal adenocarcinoma (PDAC) progression remain incompletely characterized. This study investigates their contributions to PDAC and therapeutic potential.</p><p><strong>Methods: </strong>The expressions of ligands HLA-E and galectin 9 and receptors NKG2A and TIM3 were analyzed through bioinformatics, immunohistochemistry, and flow cytometry. Effects of HLA-E and galectin 9 overexpression on pancreatic epithelial cells were assessed by Transwell, wound healing, and CCK-8 assays. Ligand-receptor interactions and their impact on lymphocyte function were examined by multiplex immunofluorescence, single-cell RNA-sequencing, and functional assays.</p><p><strong>Results: </strong>The expression of ligands HLA-E and galectin 9 was elevated in PDAC cancer tissues compared with both normal tissues and benign lesions. The overexpression of HLA-E enhanced the migratory and invasive ability of pancreatic epithelial cells. Moreover, the high expression of HLA-E and galectin 9 correlated with worse overall survival in PDAC patients. Mechanistically, increased NKG2A expression in both tumor stroma and parenchyma was associated with impaired function of tumor-infiltrating T cells and NK cells. Spatial analyses further revealed colocalization of NKG2A⁺ T cells with high HLA-E-expressing tumor regions, indicating an active and localized immunosuppressive circuit. Single-cell profiling showed that NKG2A⁺ and TIM3⁺ tumor-infiltrating T cells exhibited exhausted signatures, particularly when co-expressing PD-1. Importantly, dual blockade of NKG2A or TIM3 with PD-1 enhanced the anti-tumor response of CD8⁺ and CD4⁺ T cells, mediated by SHP-1 inhibition and ERK activation.</p><p><strong>Conclusions: </strong>This study identifies NKG2A-HLA-E and TIM3-galectin 9 pathways as key mechanisms in PDAC progression and immune inhibition and provides a mechanistic rationale for combining their blockade with PD-1-PD-L1 blockade as a potential therapeutic strategy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379495","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":"Integrative analysis of small cell carcinoma of the uterine cervix reveals its heterogeneity and provides novel predictive markers.","authors":"Qingxin Zhang, Jianjiang Fu, Liuying Zhong, Ziyang Yang, Can Weng, Xin Zhong, Shun Fang, Shaoyan Liu, Tonghui Cai, Xiujie Sheng, Hongyi Gao, Juan Peng","doi":"10.1007/s00262-026-04459-z","DOIUrl":"https://doi.org/10.1007/s00262-026-04459-z","url":null,"abstract":"<p><p>Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing (WES), single-cell RNA-seq (scRNA-seq), PinpoRNA-HPV, bulk RNA-sequencing, and immunohistochemistry (IHC), we delineated its molecular architecture. Genomic profiling unveiled the dysregulation of 10 core oncogenic pathways and an exceptionally high tumor mutational burden (TMB), along with frequent alterations in DNA repair genes. ScRNA-seq analysis identified nine distinct malignant subclusters characterized by lineage plasticity (ASCL1/NEUROD1/UCHL1) alongside active HPV18 transcription. The tumor microenvironment exhibited a paradoxical immune landscape: dense infiltration of CD8+ T cells and CD163+ tumor-associated macrophages (TAMs) in the complete absence of tumoral PD1/PD-L1 expression. Cell-cell communication analysis revealed that malignant subclusters specifically overexpress CD47, engaging SIRB1 on TAMs and SIRPG on T cells. IHC validation confirmed a CD8+/CD163+/PD-L1-phenotype and demonstrated that transcriptional CD47 enrichment in malignant clones implicated the CD47-SIRB1 axis as the primary immune checkpoint. These findings indicated UCSCC as an HPV-driven, heterogeneous tumor that might employ CD47 as an alternative immune evasion pathway in the absence of PD-L1, providing a strong rationale for exploring CD47 blockade as a novel potentially therapeutic strategy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379336","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":"EGFRxCD16 bispecific antibodies orchestrate superior NK cell-mediated lysis of ovarian cancer and NSCLC cell lines in combination with oncolytic viruses.","authors":"Sarah Gahbauer, Thomas Poiret","doi":"10.1007/s00262-026-04470-4","DOIUrl":"10.1007/s00262-026-04470-4","url":null,"abstract":"<p><p>Combination therapy integrating bispecific antibody (BsAb) and oncolytic viruses (OVs) to enhance antitumor immune response offers a promising therapeutic approach in comparison with OV treatment alone. This study aims to strengthen and characterize NK cell-mediated antitumor responses using modified oncolytic viruses, i.e., ONCOS-102 and ONCOS-204 genetically engineered to express Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and the ligand of inducible T-cell co-stimulator (ICOSL), respectively, in combination with a BsAb targeting CD16 and the epidermal growth factor receptor (EGFR). Changes in phenotype, degranulation, cytokine production, and cytotoxicity of NK cells induced by combined treatment were compared with those induced by individual treatment strategies against non-small cell lung cancer, malignant melanoma, and ovarian cancer. Using flow cytometry and colorimetry-based cytotoxic assays, our results showed that EGFRxCD16 BsAb was the main variable in driving NK cells toward an activated phenotype and enhanced NK function; while the OVs alone did not demonstrate drastic impact on NK cells. Interestingly, tumor preconditioning with OVs in combination with EGFRxCD16 BsAb showed the most potent NK cytotoxicity in comparison with EGFRxCD16 BsAb alone and appeared to synergize best against ovarian and EGFRmut lung tumor cell lines. Despite differences between tumor types, our data suggest a favorable interplay between OVs, especially ONCOS-102, and EGFRxCD16 BsAb  in sensitizing NK cell antitumor response in vitro. These results warrant further in vivo exploration and clinical translation of this promising combination of therapeutic modalities.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 7","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379515","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":"Transcriptomic landscape of peripheral T cells following CAR-T cell therapy in diffuse large B cell lymphoma.","authors":"Ismael de la Iglesia-San Sebastián, Sara Fernández de Córdoba-Oñate, Mariana Bastos-Oreiro, Raquel Fernández-González, Miguel López-Esteban, Rebeca Bailén, Ignacio Gómez-Centurión, Dolores Fuentes, Javier Anguita, Mi Kwon, Ramón García-Sanz, Ismael Buño, Carolina Martínez-Laperche","doi":"10.1007/s00262-026-04444-6","DOIUrl":"10.1007/s00262-026-04444-6","url":null,"abstract":"<p><strong>Background: </strong>CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contribute to this heterogeneity, but the underlying transcriptional programs are incompletely defined.</p><p><strong>Methods: </strong>We performed RNA-sequencing of CD3⁺ T cells from 26 LBCL patients at two time points-pre-apheresis (PA; n = 23) and day 14 post-infusion (D14; n = 9)-and applied differential expression, gene set enrichment analysis (GSEA), and gene regulatory network inference.</p><p><strong>Results/interpretation: </strong>In PA T cells, we identified 320 differentially expressed genes enriched for immune-related programs (TCR signaling, T cell differentiation, IL-2-related signaling, TCR regulation of apoptosis and misregulation of cancer) and signatures consistent with immune dysfunction. Unsupervised clustering defined two LBCL T cell expression profiles, which were strongly associated with early disease progression (91% vs 16%; P < 0.001), supporting a hyperactivated yet progressively dysfunctional T cell state that may compromise CAR-T fitness and persistence. At the pathway level, GSEA in LBCL PA T cells showed enrichment of PI3K/AKT/mTOR and MYC target programs together with apoptosis-related signatures.</p><p><strong>Conclusions: </strong>Transcriptomic heterogeneity in endogenous T cells is strongly linked to early post-CAR-T progression and may inform strategies to optimize CAR-T persistence and efficacy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148371718","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":"HMGB1 ubiquitination inhibition and extracellular secretion, mediated by m⁶A modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells and tumor cells to aggravate acute lymphoblastic leukemia.","authors":"Xiaofang Hong, Daiyan Yang, Jianhao Xing, Huihui Li, Jifu Zheng","doi":"10.1007/s00262-026-04413-z","DOIUrl":"10.1007/s00262-026-04413-z","url":null,"abstract":"<p><strong>Background: </strong>MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MALAT1 in chemoresistance and malignant growth of ALL cells, as well as its underlying mechanisms.</p><p><strong>Methods: </strong>The expression of target molecules was evaluated by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical staining. CCK-8, EdU staining and flow cytometry were conducted to determine cell proliferation and apoptosis. RIP, RNA-pull down, Co-IP, and MeRIP were used to investigate molecular mechanisms. ALL cells were injected into nude mice to evaluate in vivo tumor formation.</p><p><strong>Results: </strong>MALAT1 and methyltransferase-like 14 (METTL14) were up-regulated in ALL, which exhibited a positive correlation. METTL14-mediated m⁶A modification raised MALAT1 stability and expression, and consequently facilitated ALL cell growth and apoptosis inhibition. Furthermore, MALAT1 was packaged into ALL cells-derived exosomes by hnRNPA2B1, and then transferred to NK92-MI cells. Exosomal MALAT1 suppressed tripartite motif-containing 27 (TRIM27)-mediated ubiquitination of High-mobility group box 1 (HMGB1) in NK92-MI cells, thereby leading to adriamycin resistance and malignant development of ALL cells.</p><p><strong>Conclusion: </strong>ALL cells-derived exosomal MALAT1 was up-regulated by METTL14-mediated m⁶A modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells. Therefore, inhibition of METTL14/MALAT1/HMGB1 axis might be a therapeutic strategy for ALL patients.</p><p><strong>Highlights: </strong>(1) METTL14 and MALAT1 were positively correlated in ALL samples. (2) METTL14 increased MALAT1 stability and expression in an IGF2BP1-mediated m6A manner. (3) ALL cells transferring exosomal MALAT1 suppressed TRIM27-mediated HMGB1 ubiquitination in NK92-MI cells. (4) HMGB1 silencing in NK92-MI cells enhanced adriamycin sensitivity of ALL cells. (5) MALAT1/HMGB1 axis inhibition delayed in vivo ALL growth via NK cell activation.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148371693","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":"Downregulation of ANKRD22 promotes ovarian cancer cell proliferation by enhancing the immunosuppressive capacity of M-MDSCs.","authors":"Huanhuan Chen, Tianhui Pan, Qionghua He, Shu Yu Li, Jing Fei, Jianwei Zhou, Dandan Zhong","doi":"10.1007/s00262-026-04405-z","DOIUrl":"10.1007/s00262-026-04405-z","url":null,"abstract":"<p><p>ANKRD22 is a protein involved in tumor immune regulation. To elucidate its role in ovarian cancer, we analyzed its expression pattern and association with the tumor immune microenvironment. Bioinformatics analyses revealed upregulation of ANKRD22 in ovarian cancer tissues compared with normal controls. High ANKRD22 expression correlated with favorable patient prognosis, suggesting its potential as a prognostic biomarker. In vitro experiments using the ID8 murine ovarian cancer cell line, selected for its relevance to immunocompetent mouse models in tumor microenvironment studies, revealed that ANKRD22 expression is regulated by the tumor microenvironment. Monocytic myeloid-derived suppressor cells (M-MDSCs) with Ankrd22 knockout exhibited enhanced immunosuppressive function, inhibited T lymphocyte proliferation and reduced IL-2 secretion. These M-MDSCs promoted ovarian cancer cell proliferation primarily through direct contact. RNA sequencing suggested that Ankrd22 might regulate the immunosuppressive function of M-MDSCs by modulating fatty acid metabolism. In vivo rescue experiments in a subcutaneous tumor model confirmed that Ankrd22 mediates the protumor effect of M-MDSCs. In summary, this study demonstrated that downregulation of ANKRD22 promotes ovarian cancer progression by enhancing the immunosuppressive function of M-MDSCs, providing a theoretical basis for targeting ANKRD22 in ovarian cancer treatment.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"75 7","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355506","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":"R-5780, a SagA-engineered Lactococcus lactis, is a safe oral synthetic-biology microbial therapy that potentiates PD-1 blockade.","authors":"Miaki Fukuhara, Bikash Sahay, Gary R Fanger, Christian Furlan Freguia","doi":"10.1007/s00262-026-04480-2","DOIUrl":"10.1007/s00262-026-04480-2","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have transformed cancer therapy, yet response rates remain limited across solid tumors. Modulation of the gut microbiome has emerged as a promising strategy to enhance immunotherapy efficacy. R-5780 is an engineered Lactococcus lactis strain expressing the peptidoglycan hydrolase Secreted Antigen A (SagA), which generates muramyl dipeptide (MDP), a natural ligand of the nucleotide-binding oligomerization domain 2 (NOD2) receptor involved in innate immune activation and antigen-presenting cell maturation. Therapeutic potential of R-5780 was assessed in vivo murine models. Using the CT26 murine colorectal carcinoma model, oral administration of R-5780 with anti-PD-1 significantly inhibited tumor growth in both prophylactic and therapeutic settings compared to ICI therapy alone. Mechanistic studies revealed that R-5780 enhanced dendritic-cell activation and promoted a pro-inflammatory tumor microenvironment characterized by elevated interleukin-1 beta (IL-1β). Multiplex cytokine profiling and flow cytometry further showed that R-5780 reduced CD8⁺ T-cell exhaustion, with decreased expression of PD-1, LAG-3, and TIM-3 on intratumoral T cells. In murine toxicology studies, R-5780 was well tolerated, with no adverse events or systemic inflammation observed following oral administration. Together, these results identify R-5780 as a safe and potent NOD2 activator that synergizes with PD-1 blockade to enhance antitumor immunity and support its advancement toward clinical evaluation.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355488","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}