Decoding the PTM code of cGAS-STING in gastric cancer: from innate DNA sensing to precision combination therapy

The cGAS-STING pathway represents a crucial component of innate immune responses and has been increasingly recognized as a pivotal regulatory mechanism governing gastric cancer progression and therapeutic resistance. This comprehensive review synthesizes current knowledge regarding the mechanisms through which Post-Translational Modifications (PTMs) modulate the activity, stability, and subcellular localization of cGAS and STING proteins, encompassing phosphorylation, ubiquitination, acetylation, SUMOylation, and palmitoylation. These PTMs function as pivotal regulators that maintain the delicate balance between immune activation and suppression within the tumor microenvironment, directly influencing tumor immune evasion, proliferation, and metastatic potential. Furthermore, we critically examine the dual role of the cGAS-STING pathway in gastric cancer, highlighting its context-dependent anti-tumor and pro-tumor effects. We also investigate potential therapeutic strategies targeting post-translational modifications to restore or potentiate cGAS-STING signaling, which could substantially enhance the efficacy of chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Our comprehensive analysis underscores the substantial prognostic and therapeutic promise of PTM-directed interventions for gastric cancer management, providing a valuable foundation for future mechanistic research and clinical translation.