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

IF 22.6 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2026-06-30 DOI:10.1158/0008-5472.can-25-5286

Liang Zhang, Xiang Zheng, Haotian Fu, Long Liu, Wei Zhang, Yuanbiao Zhang, Zhenzhen Gao, Sitong Zhang, Yitian Jin, Sheng Yan

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引用次数: 0

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.

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抑制PPM1D干扰线粒体完整性，刺激cGAS-STING信号传导和抗肿瘤免疫

免疫检查点阻断（ICB）是治疗肝细胞癌（HCC）的一种重要方法。然而，对ICB治疗的耐药性仍然具有挑战性。在这里，我们发现蛋白磷酸酶镁依赖性1δ (PPM1D)是HCC免疫治疗耐药的驱动因素。PPM1D在肿瘤组织中表达显著上调，肿瘤细胞通过TNFα-NF-κB信号激活效应CD8+ T淋巴细胞，从而使PPM1D表达升高。遗传或药理抑制PPM1D通过增强CD8+ t细胞毒性来抑制HCC进展。机制上，PPM1D通过直接去磷酸化线粒体外膜组分VDAC2 Ser 115，阻止VDAC2寡聚化，维持肿瘤细胞线粒体稳态，限制线粒体DNA泄漏引发的cGAS-STING-IFN活性。抑制PPM1D与PD-1抑制在临床前HCC模型中的协同作用，毒性最小。总之，本研究为靶向PPM1D提高HCC免疫治疗疗效提供了见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.