Inhibiting PPM1D Perturbs Mitochondrial Integrity to Stimulate cGAS-STING Signaling and Antitumor Immunity
Liang Zhang1,2, Xiang Zheng1,2, Haotian Fu1,2
1Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China.
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.
Insights
Targeting PPM1D overcomes resistance to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC). Inhibiting PPM1D enhances CD8+ T-cell activity, improving immunotherapy effectiveness for HCC patients.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) is a key therapy for hepatocellular carcinoma (HCC).
- Resistance to ICB therapy poses a significant clinical challenge in HCC treatment.
- Identifying novel targets to overcome this resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To identify novel molecular drivers of immunotherapy resistance in HCC.
- To investigate the role of PPM1D in HCC progression and response to ICB.
- To explore PPM1D as a potential therapeutic target for enhancing HCC immunotherapy.
Main Methods:
- Analysis of PPM1D expression in HCC tumor tissues.
- Investigating the regulation of PPM1D by TNFα-NF-κB signaling in response to CD8+ T cells.
- Utilizing genetic and pharmacological inhibition of PPM1D in preclinical HCC models.
- Elucidating the mechanism of PPM1D action on mitochondrial homeostasis and cGAS-STING-IFN pathway.
- Assessing the synergistic effect of PPM1D inhibition with PD-1 blockade.
Main Results:
- PPM1D expression is significantly upregulated in HCC tissues and linked to immunotherapy resistance.
- Tumor cells increase PPM1D expression upon CD8+ T cell activation via TNFα-NF-κB.
- PPM1D inhibition enhances CD8+ T cell cytotoxicity and suppresses HCC progression.
- PPM1D dephosphorylates VDAC2, maintaining mitochondrial homeostasis and suppressing cGAS-STING-IFN signaling.
- Inhibition of PPM1D synergizes with PD-1 blockade in preclinical HCC models with low toxicity.
Conclusions:
- PPM1D is a critical driver of immunotherapy resistance in hepatocellular carcinoma.
- Targeting PPM1D enhances anti-tumor immunity by improving CD8+ T cell function.
- PPM1D inhibition represents a promising strategy to improve the efficacy of ICB in HCC.
