{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T21:47:53Z","timestamp":1767995273599,"version":"3.49.0"},"reference-count":73,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170674"],"award-info":[{"award-number":["32170674"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370718"],"award-info":[{"award-number":["32370718"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immunotherapy has become a promising treatment for gastric cancer. However, its effectiveness varies significantly across subtypes because of heterogeneous immune microenvironments and genomic alterations. Here, we established Immune&amp;Driver molecular subtypes CS1 and CS2 by systematically integrating multi-omics data for immune-related and driver genes. CS1 was linked to a better prognosis, while CS2 represented a poorer prognostic phenotype. CS1 displayed enhanced genomic instability, marked by higher mutation frequency and chromosomal alterations. In contrast, CS2 exhibited higher immune activity, with a higher density of immune cell infiltration and increased expression of chemokines and immune checkpoint genes. Among FDA-approved anti-cancer agents included in a pan-cancer drug sensitivity prediction framework, CS1 was predicted to be more sensitive to conventional chemotherapeutic agents, whereas CS2 was predicted to be more responsive to immune-related agents. In melanoma datasets, a CS2-like transcriptomic pattern was associated with improved response to anti-PD-1 therapy, with the combination of anti-PD-1 and anti-CTLA-4 showing more favorable response patterns compared to anti-PD-1 monotherapy. Additionally, we developed an immunotherapy response prediction model using PCA-based logistic regression according to the transcriptional expression of CS biomarkers. The model was trained in melanoma immunotherapy cohorts and validated across independent melanoma datasets, and it further achieved a higher AUC in an external gastric cancer cohort treated with anti-PD-1 therapy. Collectively, this study highlights immune and genomic heterogeneity in gastric cancer and provides a hypothesis-generating framework for exploring immunotherapy response.<\/jats:p>","DOI":"10.3390\/ijms27020696","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T16:03:16Z","timestamp":1767974596000},"page":"696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Immune&amp;Driver Molecular Subtypes Optimizes Immunotherapy Strategies for Gastric Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Jing","family":"Gan","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangshuang","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbo","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manyi","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongle","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinrong","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbo","family":"Dong","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusen","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengmeng","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujie","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Duan","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-8945","authenticated-orcid":false,"given":"Shangwei","family":"Ning","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9103-8642","authenticated-orcid":false,"given":"Hui","family":"Zhi","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0140-6736(20)31288-5","article-title":"Gastric cancer","volume":"396","author":"Smyth","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s10120-021-01201-9","article-title":"A novel genomic classification system of gastric cancer via integrating multidimensional genomic characteristics","volume":"24","author":"Wang","year":"2021","journal-title":"Gastric 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