Liver and Bile

Gut. 2025;74(4):613-627

Tu Y, Wu H, Zhong C, Liu Y, Xiong Z, Chen S, Wang J, Wong PPC, Yang W, Liang Z, Lu J, Chen S, Zhang L, Feng Y, Si-Tou WWY, Yin B, Lin Y, Liang J, Liang L, Vong JSL, Ren W, Kwong TT, Leung H, To KF, Ma S, Tong M, Sun H, Xia Q, Zhou J, Kerr D, La Thangue N, Sung JJY, Chan SL, Cheng ASL

Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma

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: The authors aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC).
Design: They correlated the prognostic outcomes of HCC patients from a pembrolizumab trial with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. They 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 anti-tumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate signal transducer and activator of transcription 1 (STAT1)-driven anti-tumour 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 anti-tumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses.

Conclusion: This immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-Gasdermin E pyroptotic circuitry as the mechanistic basis for an ongoing phase 2 trial to tackle immune checkpoint blockade resistance.

DOI:  10.1136/gutjnl-2024-332281