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@ARTICLE{Prawira:303093,
      author       = {A. Prawira and H. Xu and Y. Mei and N. J. M. Nasir and M.
                      J. Y. Reolo and M. Otsuka and W. Q. Leow and M. Rahbari$^*$
                      and Z. Chen$^*$ and M. Weerasooriya and L. B. Abdullah and
                      J. Wu and S. N. Hazirah and M. Wasser and A. Chung and B. K.
                      Goh and P. K. Chow and S. Albani and J. Lee and T. K. H. Lim
                      and W. Zhai and Y. Y. Dan and G. B. Goh and M.
                      Heikenwälder$^*$ and Y. Zhang and R. Dasgupta and W. M. D.
                      Tai and H. Liu and J. Chen and V. Chew},
      title        = {{T}argeting {T}reg-fibroblast interaction to enhance
                      immunotherapy in steatotic liver disease-related
                      hepatocellular carcinoma.},
      journal      = {Gut},
      volume       = {nn},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2025-01518},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {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.},
      keywords     = {CELLULAR IMMUNITY (Other) / HEPATOCELLULAR CARCINOMA
                      (Other) / IMMUNOREGULATION (Other) / IMMUNOTHERAPY (Other) /
                      LIVER IMMUNOLOGY (Other)},
      cin          = {D440},
      ddc          = {610},
      cid          = {I:(DE-He78)D440-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40695620},
      doi          = {10.1136/gutjnl-2025-335084},
      url          = {https://inrepo02.dkfz.de/record/303093},
}