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| 001 | 303093 | ||
| 005 | 20250725114204.0 | ||
| 024 | 7 | _ | |a 10.1136/gutjnl-2025-335084 |2 doi |
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| 024 | 7 | _ | |a 1468-3288 |2 ISSN |
| 037 | _ | _ | |a DKFZ-2025-01518 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Prawira, Aldo |b 0 |
| 245 | _ | _ | |a Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma. |
| 260 | _ | _ | |a London |c 2025 |b BMJ Publishing Group |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 500 | _ | _ | |a epub |
| 520 | _ | _ | |a 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. |
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| 650 | _ | 7 | |a CELLULAR IMMUNITY |2 Other |
| 650 | _ | 7 | |a HEPATOCELLULAR CARCINOMA |2 Other |
| 650 | _ | 7 | |a IMMUNOREGULATION |2 Other |
| 650 | _ | 7 | |a IMMUNOTHERAPY |2 Other |
| 650 | _ | 7 | |a LIVER IMMUNOLOGY |2 Other |
| 700 | 1 | _ | |a Xu, Hang |b 1 |
| 700 | 1 | _ | |a Mei, Yu |b 2 |
| 700 | 1 | _ | |a Nasir, Nurul Jannah Mohamed |0 0000-0003-3700-9036 |b 3 |
| 700 | 1 | _ | |a Reolo, Marie J Y |b 4 |
| 700 | 1 | _ | |a Otsuka, Masayuki |b 5 |
| 700 | 1 | _ | |a Leow, Wei Qiang |b 6 |
| 700 | 1 | _ | |a Rahbari, Mohammad |0 P:(DE-He78)8757fd490dcfe2d6c4b1c2b126262468 |b 7 |u dkfz |
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| 700 | 1 | _ | |a Weerasooriya, Madhushanee |b 9 |
| 700 | 1 | _ | |a Abdullah, Liyana Bte |b 10 |
| 700 | 1 | _ | |a Wu, Jiawei |b 11 |
| 700 | 1 | _ | |a Hazirah, Sharifah N |b 12 |
| 700 | 1 | _ | |a Wasser, Martin |b 13 |
| 700 | 1 | _ | |a Chung, Alexander |b 14 |
| 700 | 1 | _ | |a Goh, Brian Kp |b 15 |
| 700 | 1 | _ | |a Chow, Pierce Kh |0 0000-0003-0584-2584 |b 16 |
| 700 | 1 | _ | |a Albani, Salvatore |b 17 |
| 700 | 1 | _ | |a Lee, Joycelyn |b 18 |
| 700 | 1 | _ | |a Lim, Tony Kiat Hon |b 19 |
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| 700 | 1 | _ | |a Zhang, Yongliang |0 0000-0002-4964-1285 |b 24 |
| 700 | 1 | _ | |a Dasgupta, Ramanuj |b 25 |
| 700 | 1 | _ | |a Tai, Wai Meng David |b 26 |
| 700 | 1 | _ | |a Liu, Haiyan |b 27 |
| 700 | 1 | _ | |a Chen, Jinmiao |b 28 |
| 700 | 1 | _ | |a Chew, Valerie |0 0000-0002-5617-0936 |b 29 |
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