Treg-directed cancer immunotherapy beyond immune checkpoints: progress and opportunities

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, a significant proportion of patients fail to respond, in part due to persistent immunosuppression mediated by regulatory T cells (Tregs). Previous efforts to target Tregs focused primarily on immune co-signaling pathways such as cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1, but these approaches resulted in limited clinical benefits, as they address only part of the biology maintaining Treg dominance within the tumor microenvironment. Consequently, recent strategies have expanded beyond co-signaling to target metabolic, cytokine, chemokine, and transcriptional pathways that may act synergistically with ICIs. In this review, we summarize the biological rationale and current clinical progress of key non-co-signaling Treg-targeting strategies, including interleukin-2/CD25, transforming growth factor-beta, forkhead box P3, CD39/CD73 adenosine axis, and C-C motif chemokine receptor 4/8 chemokine pathways. We further discuss emerging opportunities such as selectively targeting tumor-infiltrating Treg-enriched molecules, developing refined biomarkers for patient selection, and applying novel engineering modalities to improve therapeutic precision and durability across broader patient populations.