Molecular classification and precision therapy in gastric cancer: Current advances and future perspectives (Review)

Abstract

The emergence of molecular classifications for gastric cancer (GC), The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG), has advanced targeted and immunotherapies, but their clinical translation faces real-world obstacles including high cost, tissue availability, standardization, and intratumoral heterogeneity. The present review critically compares the two classification systems regarding prognostic utility across geographic populations and boundary conflicts, noting that ACRG is more operable in East Asian populations whereas TCGA is better suited for mechanistic exploration. Focusing on acquired resistance as a core bottleneck in precision therapy, mechanisms underlying anti-Human Epidermal Growth Factor Receptor 2 (HER2) resistance and primary/secondary resistance to immune checkpoint inhibitors (ICIs) were systematically dissected, while also addressing immune-related adverse events and pseudo-/hyperprogression. Moreover, non-immune elements of the tumor microenvironment deserve attention: Cancer-associated fibroblasts limit drug penetration and promote epithelial-mesenchymal transition through physical barriers and paracrine signaling; metabolic reprogramming (high glycolysis and glutamine addiction) impairs chemotherapy and ICI efficacy via an acidic microenvironment and metabolic competition. Finally, multi-target combination strategies are envisioned based on pathway redundancy, along with liquid biopsy-driven dynamic adaptive therapy and single-cell/spatial multi-omics integration for precise microenvironment intervention. The present review aims to offer a systematic reference for moving GC precision therapy from static subtyping toward dynamic, multi-dimensional integration.