Inhibiting PPM1D Perturbs Mitochondrial Integrity to Stimulate cGAS-STING Signaling and Antitumor Immunity
Liang Zhang1, Xiang Zheng2, Haotian Fu2
1Second Affiliated Hospital of Zhejiang University Hangzhou, Zhejiang China.
Abstract:
Immune checkpoint blockade (ICB) represents an important therapeutic approach for hepatocellular carcinoma (HCC). However, resistance to ICB treatment remains challenging. Here, 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 pharmacological 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.
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.
