Inhibiting PPM1D Perturbs Mitochondrial Integrity to Stimulate cGAS-STING Signaling and Antitumor Immunity

Abstract Immune checkpoint blockade (ICB) represents an important therapeutic approach for hepatocellular carcinoma (HCC). However, resistance to ICB treatment remains challenging. In this study, we identified protein phosphatase magnesium–dependent 1δ (PPM1D) as a driver of HCC immunotherapy resistance. PPM1D expression was significantly upregulated in tumor tissues, and tumor cells elevated PPM1D expression in response to effector CD8+ T lymphocyte activation via TNFα–NF-κB signaling. Genetic or pharmacologic inhibition of PPM1D inhibited HCC progression by enhancing CD8+ T-cell cytotoxicity. Mechanistically, PPM1D maintained tumor cell mitochondrial homeostasis and limited mitochondrial DNA leakage–triggered cGAS–STING–IFN activity by directly dephosphorylating mitochondrial outer membrane component VDAC2 at Ser 115, preventing VDAC2 oligomerization. Inhibiting PPM1D synergized with PD-1 inhibition in preclinical HCC models with minimal toxicity. Together, this study provides insights into targeting PPM1D to improve immunotherapy efficacy in HCC. Significance: PPM1D orchestrates mitochondrial homeostasis in hepatocellular carcinoma cells through reducing VDAC2 oligomerization to limit mitochondrial DNA leakage and prevent cGAS-STING-IFN pathway activation and antitumor immunity, revealing PPM1D as a potential immunotherapeutic target.