%0 Journal Article
%A Prawira, Aldo
%A Xu, Hang
%A Mei, Yu
%A Nasir, Nurul Jannah Mohamed
%A Reolo, Marie J Y
%A Otsuka, Masayuki
%A Leow, Wei Qiang
%A Rahbari, Mohammad
%A Chen, Ziyao
%A Weerasooriya, Madhushanee
%A Abdullah, Liyana Bte
%A Wu, Jiawei
%A Hazirah, Sharifah N
%A Wasser, Martin
%A Chung, Alexander
%A Goh, Brian Kp
%A Chow, Pierce Kh
%A Albani, Salvatore
%A Lee, Joycelyn
%A Lim, Tony Kiat Hon
%A Zhai, Weiwei
%A Dan, Yock Young
%A Goh, George Bb
%A Heikenwälder, Mathias
%A Zhang, Yongliang
%A Dasgupta, Ramanuj
%A Tai, Wai Meng David
%A Liu, Haiyan
%A Chen, Jinmiao
%A Chew, Valerie
%T Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma.
%J Gut
%V nn
%@ 0017-5749
%C London
%I BMJ Publishing Group
%M DKFZ-2025-01518
%P nn
%D 2025
%Z epub
%X Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC), a rising global challenge, is characterised by unique tumour microenvironment (TME) adaptations.This study investigates the immune microenvironment and interactions driving immunosuppression and potential resistance to immunotherapy in SLD-HCC.We employed single-cell transcriptomics, cytometry by time-of-flight (CyTOF) and two independent spatial transcriptomics platforms to study the TME of 22 SLD-HCC and 31 non-SLD-HCC cases. Findings were further validated using multiplex immunohistochemistry in an independent cohort of 103 patients, an HCC model and an immunotherapy-treated patient cohort to evaluate clinical relevance.Our findings revealed significant alterations in immune and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs), suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. CyTOF revealed a cold, immunosuppressive TME with reduced CD8+ T cells and increased Tregs. Spatial transcriptomics further highlighted distinct Treg-CAF clusters localised at tumour margins, suggesting a spatially organised immunosuppressive niche. Mechanistically, tumour necrosis factor superfamily member 14 (TNFSF14)-tumour necrosis factor receptor superfamily member 14 (TNFRSF14)-mediated Treg-CAF interaction was identified as a critical driver of immunotherapy resistance in SLD-HCC. Blocking TNFRSF14 in an HCC model fed with a high-fat diet resulted in reduced Tregs, increased active CD8+ and memory CD4+ T cells, and a synergistic effect with anti-programmed cell death protein 1 therapy to enhance antitumour immunity and overcome immunotherapy resistance in SLD-HCC.This study uncovers critical immune and metabolic adaptations in SLD-HCC, identifying TNFSF14-TNFRSF14 signalling as a key driver of immunotherapy resistance. Targeting this signalling axis enhances antitumour immunity and improves immunotherapy efficacy, offering a promising therapeutic strategy for SLD-HCC.
%K CELLULAR IMMUNITY (Other)
%K HEPATOCELLULAR CARCINOMA (Other)
%K IMMUNOREGULATION (Other)
%K IMMUNOTHERAPY (Other)
%K LIVER IMMUNOLOGY (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40695620
%R 10.1136/gutjnl-2025-335084
%U https://inrepo02.dkfz.de/record/303093