{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:45:54Z","timestamp":1782801954702,"version":"3.54.5"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Although immune checkpoint blockade (ICB) has changed treatment strategies for gastric adenocarcinoma (STAD), many patients show primary resistance. Tumor-intrinsic transcriptional heterogeneity may contribute to immune escape, but the malignant-cell programs and candidate biomarkers linked to this process remain incompletely defined. Here, we integrated single-cell transcriptomic profiles of 162,116 cells from 35 STAD samples with multiple bulk transcriptomic cohorts to characterize malignant-cell regulatory programs. Non-negative matrix factorization identified meta-program 2 (MP2), a malignant-cell program closely associated with immune-escape signatures. Through integrated co-expression analysis and machine-learning-based prioritization, RNASE1 was identified as an MP2-related candidate biomarker. High RNASE1 expression was associated with poor survival, higher immune and stromal scores, increased immune-checkpoint expression, and enrichment of ICB-response-related transcriptomic signatures.\n                    <jats:italic>In vitro<\/jats:italic>\n                    RNASE1 knockdown reduced STAD cell proliferation, migration, and invasion, supporting a functional contribution to malignant cellular phenotypes. Together, these findings suggest that RNASE1 is an immune-evasion-associated biomarker with potential value for prognosis and ICB-response stratification in STAD, while prospective clinical and\n                    <jats:italic>in vivo<\/jats:italic>\n                    validation remain necessary.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1884482","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:17:56Z","timestamp":1782800276000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-intrinsic immune-genetic dynamics identify RNASE1 as an immune-evasion-associated biomarker and predictor of checkpoint blockade response in gastric adenocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Haoyun","family":"Xia","sequence":"first","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxing","family":"Guo","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajia","family":"Lin","sequence":"additional","affiliation":[{"name":"Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Guo","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Tian","sequence":"additional","affiliation":[{"name":"Fujian Medical University Union Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenshen","family":"Huang","sequence":"additional","affiliation":[{"name":"Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangqin","family":"Xue","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqi","family":"Chen","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.20034","article-title":"Gastric cancer: a review","volume":"335","author":"Patel","year":"2026","journal-title":"Jama"},{"key":"B2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13045-024-01578-x","article-title":"Recent developments in immunotherapy for gastrointestinal tract cancers","volume":"17","author":"Chong","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Dagogo-Jack","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.08.005","article-title":"Cancer cell states: lessons from ten years of single-cell RNA-sequencing of human tumors","volume":"42","author":"Tirosh","year":"2024","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01111-8","article-title":"Cancer immune evasion, immunoediting and intratumour heterogeneity","volume":"25","author":"Roerden","year":"2025","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature08460","article-title":"Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1","volume":"462","author":"Barbie","year":"2009","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3850","article-title":"Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes","volume":"21","author":"Cristescu","year":"2015","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30108-6","article-title":"Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis","volume":"19","author":"Cheong","year":"2018","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.730","article-title":"Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA sequencing","volume":"12","author":"Jiang","year":"2022","journal-title":"Clin Transl Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0683","article-title":"Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer","volume":"12","author":"Kumar","year":"2022","journal-title":"Cancer Discov"},{"key":"B11","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.21037\/tcr-23-2295","article-title":"The prognostic value of immune escape-related genes in lung adenocarcinoma","volume":"13","author":"Jia","year":"2024","journal-title":"Transl Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/s41586-023-06130-4","article-title":"Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours","volume":"618","author":"Gavish","year":"2023","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100498","article-title":"hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data","volume":"3","author":"Morabito","year":"2023","journal-title":"Cell Rep Methods"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00180-015-0642-2","article-title":"Boosting in Cox regression: a comparison between the likelihood-based and the model-based approaches with focus on the R-packages CoxBoost and mboost","volume":"31","author":"De Bin","year":"2016","journal-title":"Comput Stat"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1201\/9781003493679-19","article-title":"Random survival forests","volume":"2","author":"Ishwaran","year":"2008","journal-title":"Ann Appl Stat"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"B19","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","article-title":"Molecular and genetic properties of tumors associated with local immune cytolytic activity","volume":"160","author":"Rooney","year":"2015","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI91190","article-title":"IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/srep00765","article-title":"12-chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy","volume":"2","author":"Messina","year":"2012","journal-title":"Sci Rep"},{"key":"B24","doi-asserted-by":"publisher","first-page":"eaah3560","DOI":"10.1126\/scitranslmed.aah3560","article-title":"Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance","volume":"9","author":"Roh","year":"2017","journal-title":"Sci Transl Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8399","article-title":"Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy","volume":"355","author":"Davoli","year":"2017","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.cell.2018.09.006","article-title":"A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade","volume":"175","author":"Jerby-Arnon","year":"2018","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2174\/1874467216666230322113039","article-title":"CD73 blockade alleviated hepatic fibrosis via inhibiting hepatic stellate cells proliferation and activation","volume":"17","author":"Yang","year":"2024","journal-title":"Curr Mol Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1186\/s12943-024-02169-7","article-title":"Uncovering the predictive and immunomodulatory potential of transient receptor potential melastatin family-related CCNE1 in pan-cancer","volume":"23","author":"Zhang","year":"2024","journal-title":"Mol Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404961","article-title":"Ribonuclease 1 induces T-cell dysfunction and impairs CD8(+) T-cell cytotoxicity to benefit tumor growth through hijacking STAT1","volume":"12","author":"Yang","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7150\/thno.60540","article-title":"Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer","volume":"12","author":"Li","year":"2022","journal-title":"Theranostics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.576491","article-title":"Endothelial ribonuclease 1 in cardiovascular and systemic inflammation","volume":"8","author":"Bedenbender","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/s41392-025-02206-x","article-title":"RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer","volume":"10","author":"Zha","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3593","article-title":"Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy","volume":"362","author":"Cristescu","year":"2018","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1884482\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:17:57Z","timestamp":1782800277000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1884482\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2026.1884482"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1884482","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]},"article-number":"1884482"}}