The IL‐33/ST2 signaling axis plays a crucial role in shaping the tumor microenvironment, primarily by promoting immune suppression through tumor‐infiltrating regulatory T ( T reg ) cells. Elevated IL‐33 levels are associated with poor prognosis in multiple cancers, as IL‐33 enhances T reg stability, proliferation, and suppressive function, thereby dampening antitumor immunity. In this study, we present the rational design and biological evaluation of novel small‐molecule inhibitors targeting IL‐33/ST2 signaling to suppress T reg ‐mediated immune evasion. Guided by structure‐based drug design, we identified oxazolo5,4‐ d pyrimidine derivatives capable of forming key hydrogen bonds within the IL‐33 binding pocket, thereby enhancing binding affinity. In vitro and ex vivo assays using T‐Cell Receptor(TCR)‐stimulated human T reg cells demonstrated that these compounds significantly suppressed IL‐33‐induced T reg activation and proliferation. Notably, KYH1942 showed the most potent activity, reducing IL‐33‐induced Foxp3 and Ki‐67 expression in a dose‐dependent manner, indicative of impaired T reg function. It is worth noting that the inhibitory activities of our compounds are comparable to that of a neutralizing ST2 antibody. To our knowledge, this is the first report demonstrating that small‐molecule IL‐33 blockade can directly suppress T regs , including IL‐33‐driven Foxp3 and Ki‐67 expression. These findings establish a novel immunotherapeutic strategy targeting IL‐33‐mediated immune suppression.
Younghoon et al. (Sun,) studied this question.