{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:04:04Z","timestamp":1771567444551,"version":"3.50.1"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"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":"\n Background<\/jats:title>\n The tumor microenvironment (TME) plays a pivotal role in the progression of gastric cancer (GC) and its response to treatment, particularly by modulating parthanatos (PA). However, the prognostic significance of TME and PA, as well as their potential roles in immunotherapy for GC, remain incompletely understood.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Using publicly available data, an initial gene screening was combined with differential expression analysis and univariate Cox regression to identify prognostic markers associated with TME and PA. A comprehensive machine learning framework, testing 101 algorithm combinations across 10 methodologies, was then applied. Model selection prioritized C-index performance, with the final model enabling effective patient risk stratification, as validated by Receiver Operating Characteristic (ROC) curves. Multivariate analysis subsequently identified independent prognostic factors, which were used to construct a clinical nomogram. Immune characteristics across different risk groups were compared, immunofluorescence staining of gastric cancer and paired paracancerous tissues assessed immune cell infiltration and prognostic gene-monocyte correlation. Biomarker expression patterns were confirmed\n via<\/jats:italic>\n Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) validation. Immunohistochemical (IHC) detected\n CD36<\/jats:italic>\n \/\n KIT<\/jats:italic>\n protein expression. CCK-8, Transwell and flow cytometry evaluated proliferation, migration and apoptosis in\n CD36<\/jats:italic>\n \/\n KIT<\/jats:italic>\n inhibitor-treated GC MKN45 cells. Enzyme-linked immunosorbent assay (ELISA) measured TNF-\u03b1, IFN-\u03b3, IL-10 secretion; immunofluorescence determined PARP-1\/AIFM1 subcellular localization post-inhibitor treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The multi-algorithm analysis identified the RSF-plsRcox hybrid model as the most accurate, consistently achieving C-index values greater than 0.6 across all datasets. This model identified seven clinically significant genes (\n EGF<\/jats:italic>\n ,\n PCOLCE2<\/jats:italic>\n ,\n CD36<\/jats:italic>\n ,\n ADAMTS8<\/jats:italic>\n ,\n CIDEC<\/jats:italic>\n ,\n KIT<\/jats:italic>\n , and\n AKAP12<\/jats:italic>\n ) with notable prognostic value in GC progression. The developed risk model demonstrated good predictive performance, with areas under the curve (AUCs) of 0.65, 0.68, and 0.60 at 1, 3, and 5 years, respectively. A nomogram based on independent prognostic factors\u2014risk scores, age, N stage, and M stage\u2014showed strong predictive accuracy, with AUCs of 0.72, 0.75, and 0.71 at 1, 3, and 5 years, respectively. Furthermore, distinct immune landscapes were observed between high-risk and low-risk groups, characterized by differences in immune infiltration, immune checkpoint expression, and TIDE scores. Gastric cancer tissues had reduced CD3\n +<\/jats:sup>\n T, CD3\n +<\/jats:sup>\n CD4\n +<\/jats:sup>\n T cells and M1 macrophage infiltration, increased M2 macrophages and CD14\n +<\/jats:sup>\n monocytes; AKAP12 was positively correlated with monocytes. The higher-risk group exhibited suppressed immune responses and enhanced immune evasion capabilities. RT-qPCR validation revealed significant differential expression of\n PCOLCE2<\/jats:italic>\n ,\n CD36<\/jats:italic>\n ,\n ADAMTS8<\/jats:italic>\n , and\n KIT<\/jats:italic>\n in the control group, while\n AKAP12<\/jats:italic>\n was more highly expressed in the GC group. These five prognostic genes showed significant expression differences between the two groups (\n P<\/jats:italic>\n &lt; 0.05).\n CD36<\/jats:italic>\n and\n KIT<\/jats:italic>\n protein expression was elevated in gastric cancer tissues.\n CD36\/KIT<\/jats:italic>\n inhibition downregulated their expression in MKN45 cells, inhibiting proliferation, migration and promoting apoptosis. Inhibition increased TNF-\u03b1, IFN-\u03b3 secretion, decreased IL-10, enhanced nuclear PARP-1 fluorescence and AIFM1 nuclear translocation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study innovatively integrated TME-RGs and PA-RGs to construct a machine learning GC prognostic model (7 key genes:\n EGF<\/jats:italic>\n ,\n PCOLCE2<\/jats:italic>\n ,\n CD36<\/jats:italic>\n ,\n ADAMTS8<\/jats:italic>\n ,\n CIDEC<\/jats:italic>\n ,\n KIT<\/jats:italic>\n , and\n AKAP12<\/jats:italic>\n ). High-risk patients had immunosuppressive TME and poor immunotherapy response, with Imatinib\/PLX4720 showing potential efficacy.\n CD36\/KIT<\/jats:italic>\n overexpression promoted GC malignancy; their inhibition remodeled TME cytokines and, for the first time, activated the PA pathway to induce GC cell death.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1636331","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:04Z","timestamp":1771564864000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic integration of tumor microenvironment and parthanatos-related genes in gastric cancer: a machine learning-driven risk model and immune landscape profiling"],"prefix":"10.3389","volume":"17","author":[{"given":"Lei","family":"Liu","sequence":"first","affiliation":[{"name":"Central Laboratory, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v29.i16.2452","article-title":"Updates on global epidemiology, risk and prognostic factors of gastric cancer","volume":"29","author":"Yang","year":"2023","journal-title":"World J Gastroenterol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 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