This study reveals the interaction mechanism between regulatory T cells (Treg) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment of steatotic liver disease-related hepatocellular carcinoma. Targeting the TNFSF14-TNFRSF14 signaling pathway can effectively enhance antitumor immune responses, providing a theoretical basis for developing novel combination immunotherapy strategies.
Literature Overview
The study titled 'Targeting Treg–fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma', published in Gut, systematically reviews and summarizes the characteristics of the tumor microenvironment in steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) and its impact on immunotherapy response. Utilizing single-cell transcriptomics, cytometry by time-of-flight (CyTOF), and spatial transcriptomics, the research comprehensively analyzed microenvironmental differences between 22 SLD-HCC and 31 non-SLD-HCC cases. Key signaling pathways were further validated through multiplex immunohistochemistry, mouse models, and immunotherapy patient cohorts.Background Knowledge
Steatotic liver disease (SLD) is a significant predisposing factor for hepatocellular carcinoma (HCC), and its metabolic and immunological microenvironmental adaptations contribute to resistance to immunotherapy. Treg cells and CAFs are recognized as core immunosuppressive cell types, yet their specific interaction mechanisms in SLD-HCC remain unclear. This study focuses on the TNFSF14-TNFRSF14 signal axis to elucidate its role in Treg-CAFs interaction and to explore whether targeting this pathway can enhance the efficacy of immune checkpoint blockade therapy. The study also evaluates molecular features such as Wnt signaling activity and neoantigen load, integrating findings from high-fat diet mouse models and anti-PD-1 treatment responses, to identify new intervention targets for immunotherapy resistance in SLD-HCC.
Research Methods and Experiments
The study included 22 SLD-HCC and 31 non-SLD-HCC patients, with 2–5 systematic tissue samplings per tumor to evaluate intratumoral heterogeneity. Using single-cell RNA sequencing (scRNA-seq), CyTOF-based immune cell profiling, spatial transcriptomics (Visium and CosMx), and multiplex immunofluorescence (mIF), the research systematically analyzed cellular composition, gene expression, ligand–receptor interaction networks, and their spatial distribution within the tumor microenvironment. Additionally, a high-fat diet-induced HCC mouse model was developed to evaluate antitumor immune responses following treatment with anti-TNFRSF14 antibodies alone or in combination with anti-PD-1 therapy.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a new molecular explanation for immunotherapy resistance in steatotic liver disease-related HCC and proposes targeting the TNFSF14-TNFRSF14 axis as a potential therapeutic strategy. Future studies should further evaluate the predictive value of this pathway in clinical settings and explore its synergistic interactions with other immune checkpoint pathways. Additionally, integrating spatial transcriptomic and metabolomic data may facilitate the development of personalized immunomicroenvironment modulation approaches.
Conclusion
By employing multi-omics and spatial transcriptomic techniques, this study systematically uncovered the spatial interaction network between Treg and cancer-associated fibroblasts in steatotic liver disease-related hepatocellular carcinoma, identifying the TNFSF14-TNFRSF14 signaling pathway as a key driver of immune suppression. Blocking this pathway effectively remodels the immune microenvironment and enhances anti-PD-1 therapeutic response, offering a new target for precision immunotherapy in SLD-HCC patients. These findings deepen our understanding of immune escape mechanisms in SLD-HCC and lay the foundation for developing combination therapies targeting the Treg-CAFs axis.
