| Summary: | <p><strong>Background</strong> Foxp3<sup>+</sup> regulatory T (T<sub>reg</sub>) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting T<sub>reg</sub> fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers.</p>
<p><strong>Methods</strong> We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and T<sub>reg</sub> instability by repressing <em>Usp21</em> gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in T<sub>reg</sub> cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy.</p>
<p><strong>Results</strong> Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to <em>Usp21</em> gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of T<sub>reg</sub> cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen T<sub>reg</sub> cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8<sup>+</sup> T cells’ production of IFN-γ and limited tumor growth.</p>
<p><strong>Conclusion</strong> Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3<sup>lo</sup> T<sub>reg</sub> cells.</p>
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