Cellular Senescence in Gastric Cancer: Molecular Mechanisms, Microenvironment Remodeling and Therapeutic Implications

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.