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This review synthesizes recent advances in GC research through an integrated, multidisciplinary lens, spanning tumor biology, microenvironmental dynamics, and therapeutic innovation. We first consolidate updated histopathological and molecular classification systems, highlighting oncogenic programs that underpin GC development, including Hippo\u2010YAP signaling and emerging neural\u2013stem cell interactions. We then examine the immunosuppressive tumor microenvironment, emphasizing the dynamic crosstalk among tumor\u2010associated macrophages, regulatory T cells, tertiary lymphoid structures, and cancer\u2010associated fibroblasts that collectively drive metastatic dissemination and therapeutic resistance. Emerging biomarker\u2010guided strategies, including CLDN18.2\u2010targeted therapies, dual immune checkpoint blockade, and engineered cellular therapies, are critically discussed alongside rational combination approaches designed to overcome resistance. Beyond canonical paradigms, we highlight transformative frontiers, such as cancer neuroscience, microbiome\u2010driven immune modulation, and spatially resolved multiomics technologies, that enable high\u2010resolution mapping of cellular interactions. Finally, we critically assess translational barriers, including organ\u2010specific metastatic tropism and resistance evolution, and propose that the convergence of deep molecular profiling, neural\u2010immune modulation, and AI\u2010enabled computational oncology will be central to advancing precision medicine for GC. This integrated framework aims to accelerate the development of mechanism\u2010based combination therapies.<\/jats:p>","DOI":"10.1002\/mco2.70772","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T07:29:17Z","timestamp":1779521357000},"source":"Crossref","is-referenced-by-count":0,"title":["Gastric Cancer: Pathobiology and Therapeutics"],"prefix":"10.1002","volume":"7","author":[{"given":"Ruixian","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences Department of General Surgery, QingPu Branch of Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology Tongji University Cancer Center, School of Medicine, Tongji 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