Targeting JMJD1C to selectively disrupt tumor T_reg cell fitness enhances antitumor immunity

Regulatory T (T_reg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving T_reg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral T_reg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral T_reg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor T_reg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor T_reg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral T_reg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor T_reg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor T_reg cells without affecting systemic immune homeostasis.