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000303093 1001_ $$aPrawira, Aldo$$b0
000303093 245__ $$aTargeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma.
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000303093 520__ $$aSteatotic 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.
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000303093 650_7 $$2Other$$aCELLULAR IMMUNITY
000303093 650_7 $$2Other$$aHEPATOCELLULAR CARCINOMA
000303093 650_7 $$2Other$$aIMMUNOREGULATION
000303093 650_7 $$2Other$$aIMMUNOTHERAPY
000303093 650_7 $$2Other$$aLIVER IMMUNOLOGY
000303093 7001_ $$aXu, Hang$$b1
000303093 7001_ $$aMei, Yu$$b2
000303093 7001_ $$00000-0003-3700-9036$$aNasir, Nurul Jannah Mohamed$$b3
000303093 7001_ $$aReolo, Marie J Y$$b4
000303093 7001_ $$aOtsuka, Masayuki$$b5
000303093 7001_ $$aLeow, Wei Qiang$$b6
000303093 7001_ $$0P:(DE-He78)8757fd490dcfe2d6c4b1c2b126262468$$aRahbari, Mohammad$$b7$$udkfz
000303093 7001_ $$0P:(DE-He78)082bd20cf7f7f960ee6c34523e1778a1$$aChen, Ziyao$$b8$$udkfz
000303093 7001_ $$aWeerasooriya, Madhushanee$$b9
000303093 7001_ $$aAbdullah, Liyana Bte$$b10
000303093 7001_ $$aWu, Jiawei$$b11
000303093 7001_ $$aHazirah, Sharifah N$$b12
000303093 7001_ $$aWasser, Martin$$b13
000303093 7001_ $$aChung, Alexander$$b14
000303093 7001_ $$aGoh, Brian Kp$$b15
000303093 7001_ $$00000-0003-0584-2584$$aChow, Pierce Kh$$b16
000303093 7001_ $$aAlbani, Salvatore$$b17
000303093 7001_ $$aLee, Joycelyn$$b18
000303093 7001_ $$aLim, Tony Kiat Hon$$b19
000303093 7001_ $$aZhai, Weiwei$$b20
000303093 7001_ $$aDan, Yock Young$$b21
000303093 7001_ $$aGoh, George Bb$$b22
000303093 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b23$$udkfz
000303093 7001_ $$00000-0002-4964-1285$$aZhang, Yongliang$$b24
000303093 7001_ $$aDasgupta, Ramanuj$$b25
000303093 7001_ $$aTai, Wai Meng David$$b26
000303093 7001_ $$aLiu, Haiyan$$b27
000303093 7001_ $$aChen, Jinmiao$$b28
000303093 7001_ $$00000-0002-5617-0936$$aChew, Valerie$$b29
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