Small molecule inhibitors targeting regulatory T cells for cancer treatment

Regulatory T cells (Tregs) are important controllers of the immune system homeostasis by preventing disproportionate immune responses. In the context of cancer, Tregs contribute to tumor development by suppressing other immune cells in the tumor microenvironment (TME). Infiltration of Tregs in the TME has been associated with poor prognosis in cancer patients. Thus, understanding the mechanisms underlying Treg recruitment and suppressive functions is essential for developing cancer immunotherapies to boost antitumor immune responses. While antibody-based strategies targeting Tregs have shown promise, small molecule inhibitors offer distinct advantages, including oral bioavailability and the ability to penetrate the TME and target intracellular proteins. Here, we provide an overview of small molecule inhibitors that have demonstrated efficacy in modulating Tregs activity in cancer and highlight the need for phenotypic assays to characterize therapeutic compounds. Small molecule inhibitors modulating different pathways involved in regulatory T cells infiltration into the tumor microenvironment, metabolism, epigenome, stability or their suppressive functions can be attractive approaches for the treatment of cancer. The combination of Treg inhibitors with other immunotherapies may become a promising strategy to boost antitumor immunity. image