Targeting regulatory T cell plasticity in gastric cancer: a unified bimodal model and precision immunotherapy paradigm: a hypothesis-generating review.

In contrast to other solid tumors, gastric cancer exhibits a particularly high dependence on regulatory T cell (Treg)-mediated immunosuppression. This reliance represents a critical driver of both primary and acquired resistance to programmed death-1/ligand-1(PD-1/PD-L1) inhibitors. By integrating existing single-cell, spatial transcriptomic, and clinical evidence, this review proposes a unified bimodal model of the Treg tumor microenvironment. Within this framework, the immune status in gastric cancer is determined by the dynamic equilibrium between immunosuppressive stable-type Tregs and pro-inflammatory fragile-type Tregs. H. pylori is posited as the master upstream regulator of this balance, capable of driving Treg differentiation toward either stability or fragility through temporally specific signaling pathways. Based on this framework, we introduce the Treg Stability-Fragility(Treg-SF) score, which incorporates Treg functional state, H. pylori infection status, and CD8+T cell density as independently weighted variables within a unified model to predict immunotherapy efficacy. Furthermore, this review outlines three mechanism-based combination therapeutic strategies that target Treg plasticity, along with a detailed preclinical validation roadmap and risk-benefit analysis. These proposals provide an actionable translational roadmap to overcome Treg-mediated immune resistance and improve clinical outcomes in gastric cancer.