TY  - JOUR
AU  - Prawira, Aldo
AU  - Xu, Hang
AU  - Mei, Yu
AU  - Nasir, Nurul Jannah Mohamed
AU  - Reolo, Marie J Y
AU  - Otsuka, Masayuki
AU  - Leow, Wei Qiang
AU  - Rahbari, Mohammad
AU  - Chen, Ziyao
AU  - Weerasooriya, Madhushanee
AU  - Abdullah, Liyana Bte
AU  - Wu, Jiawei
AU  - Hazirah, Sharifah N
AU  - Wasser, Martin
AU  - Chung, Alexander
AU  - Goh, Brian Kp
AU  - Chow, Pierce Kh
AU  - Albani, Salvatore
AU  - Lee, Joycelyn
AU  - Lim, Tony Kiat Hon
AU  - Zhai, Weiwei
AU  - Dan, Yock Young
AU  - Goh, George Bb
AU  - Heikenwälder, Mathias
AU  - Zhang, Yongliang
AU  - Dasgupta, Ramanuj
AU  - Tai, Wai Meng David
AU  - Liu, Haiyan
AU  - Chen, Jinmiao
AU  - Chew, Valerie
TI  - Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma.
JO  - Gut
VL  - nn
SN  - 0017-5749
CY  - London
PB  - BMJ Publishing Group
M1  - DKFZ-2025-01518
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
KW  - CELLULAR IMMUNITY (Other)
KW  - HEPATOCELLULAR CARCINOMA (Other)
KW  - IMMUNOREGULATION (Other)
KW  - IMMUNOTHERAPY (Other)
KW  - LIVER IMMUNOLOGY (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40695620
DO  - DOI:10.1136/gutjnl-2025-335084
UR  - https://inrepo02.dkfz.de/record/303093
ER  -