Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ([NCT03419481][1]) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ([NCT05873244][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom

中文翻译：

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STAT1-GSDME 焦亡回路的药理学激活加强了肝细胞癌的表观遗传免疫治疗


背景：基因组筛选发现免疫检查点阻断 （ICB） 难治性肿瘤中的干扰素-γ （IFNγ） 通路缺陷。然而，其非突变调节和治疗开发的可逆性仍然不太清楚。目的 我们旨在识别 ICB 耐药相关的可成药组蛋白脱乙酰酶 （HDAC），并为肝细胞癌 （HCC） 患者开发一种易于翻译的联合方法。设计 我们通过单细胞 RNA 测序将 pembrolizumab 试验 （[NCT03419481][1]） 中 HCC 患者的预后结果与所有 HDAC 亚型的肿瘤细胞表达相关联。我们使用免疫分析、单细胞多组学和染色质免疫沉淀测序研究了 4 种 ICB 耐药原位和自发模型中选择性 HDAC 抑制的治疗效果和作用机制，并通过遗传调节和共培养系统进行了验证。结果 显示较高 HDAC1 / 2 / 3 表达的 HCC 患者表现出 IFNγ 信号缺陷和 ICB 治疗中较差的生存率。选择性 I 类 HDAC 抑制剂 CXD101 的瞬时治疗使 HDAC1/2/3high 肿瘤对 ICB 疗法重新敏感，导致 CD8+T 细胞依赖性抗肿瘤和记忆 T 细胞反应。从机制上讲，CXD101 与 ICB 协同作用，通过增强染色质可及性和 IFNγ 反应基因的 H3K27 高乙酰化来刺激 STAT1 驱动的抗肿瘤免疫。IFNγ + GZMB + 细胞毒性淋巴细胞的瘤内募集进一步促进了 CXD101 诱导的 Gasdermin E （GSDME） 的切割，以 STAT1 依赖性方式触发细胞焦亡。 值得注意的是，GSDME 的缺失模拟了 STAT1 敲除，通过阻断焦亡和 IFNγ 反应来消除 CXD101-ICB 联合治疗的抗肿瘤疗效和生存获益。结论我们的免疫表观遗传学策略利用 IFNγ 介导的网络来增强癌症免疫循环，揭示了自我强化的 STAT1-GSDME 焦亡电路作为正在进行的 II 期试验的机制基础，以解决 ICB 耐药性 （[NCT05873244][2]）。数据可应合理要求提供。[1]： /lookup/external-ref？link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]： /lookup/external-ref？link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.原子