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

UNLABELLED: 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.