Regulatory T cells (Tregs) are critical immunosuppressive cells that are frequently present in the tumor microenvironment of solid cancers and enable progression of tumors toward metastasis. The cells expand in response to tumor-associated antigens and are actively involved in bypassing immunotherapy with immune checkpoint inhibitors through integrating numerous environmental signals. A point here is that Tregs are clonally distinct in peripheral blood from tumor area. Currently, an effective and novel task in cancer immunotherapy is to selectively destabilize or deplete intra-tumoral Tregs in order to avoid systemic inflammatory events. Helios is a transcription factor expressed selectively by Tregs and promotes their stabilization, and Trps1 is a master regulator of intra-tumoral Tregs. Anti-CCR8 and the IL-2Rβγ agonist Bempegaldesleukin selectively target intra-tumoral Treg population, with the former approved to not elicit autoimmunity. Disarming Treg-related immunosuppression in tumors through diverting their reprogramming or promoting naïve T cell differentiation into cells with effector immune activating profile is another promising area of research in cancer immunotherapy. Blimp-1 inhibitors and glucocorticoid-induced TNFR-related protein agonists are example approaches that can be used for diverting Treg differentiation into Th1-like CD4 T cells, thereby powering immunogenicity against cancer. Finally, selective target of intra-tumoral Tregs and their reprogramming into effector T cells is applicable using low-dose chemotherapy, and high-salt and high-tryptophan diet.
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