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

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.