Targeting regulatory T cells in gastrointestinal cancers: current status and future perspectives.

Although immune checkpoint inhibitors (ICIs) have revolutionized the gastrointestinal cancer treatment landscape, offering durable clinical benefits in a subset of patients, their efficacy remains limited to this subset of patients, underscoring the urgent need to elucidate the mechanisms underlying immune resistance and develop novel therapeutic strategies. Increasing evidence indicates that the immunosuppressive tumor immune microenvironment (TIME) is a major obstacle to effective antitumor immunity, with regulatory T cells (Tregs) emerging as the central cellular mediators of this process. Tumor-infiltrating Tregs possess potent immunosuppressive functions and suppress cytotoxic CD8+ T cell-mediated responses through multiple mechanisms, including interleukin-2 consumption, cytotoxic T-lymphocyte-associated protein 4-dependent inhibitory signaling, and secretion of immunosuppressive cytokines. Recent advances in spatial transcriptomics and single-cell technologies have catalogued substantial functional heterogeneity among Tregs and revealed their preferential accumulation at tumor margins, suggesting a potential link to immune-excluded TIME phenotypes. In this review, we summarize the known Treg-mediated immunosuppressive mechanisms in gastrointestinal cancers, highlight their spatial and functional characteristics within the TIME, and discuss the status of current Treg-targeted immunotherapeutic strategies and possible future strategies to overcome ICI resistance.