Gastric Cancer: Pathobiology and Therapeutics

Gastric cancer (GC) remains a formidable global health challenge, characterized by pronounced molecular heterogeneity, late-stage diagnosis, and limited durable responses to existing therapies. 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-YAP signaling and emerging neural-stem cell interactions. We then examine the immunosuppressive tumor microenvironment, emphasizing the dynamic crosstalk among tumor-associated macrophages, regulatory T cells, tertiary lymphoid structures, and cancer-associated fibroblasts that collectively drive metastatic dissemination and therapeutic resistance. Emerging biomarker-guided strategies, including CLDN18.2-targeted 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-driven immune modulation, and spatially resolved multiomics technologies, that enable high-resolution mapping of cellular interactions. Finally, we critically assess translational barriers, including organ-specific metastatic tropism and resistance evolution, and propose that the convergence of deep molecular profiling, neural-immune modulation, and AI-enabled computational oncology will be central to advancing precision medicine for GC. This integrated framework aims to accelerate the development of mechanism-based combination therapies.