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2026
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| Online Access: | https://doi.org/10.5281/zenodo.20390640 |
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| _version_ | 1866902230523707392 |
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| author | Fan, Xutong Zhang, Min |
| author_facet | Fan, Xutong Zhang, Min |
| contents | <p class="MsoNormal">Aberrant tumor vasculature drives a vicious cycle of severe hypoxia and immunosuppression in hepatocellular carcinoma (HCC), creating a formidable physical and biological barrier to effective therapy. However, the upstream epigenetic master regulators dictating this pathological vascular-immune crosstalk remain largely undefined. Here, we identify the chromatin remodeler CHD6 as a critical driver of the immunosuppressive HCC microenvironment. CHD6 is significantly upregulated in human HCC, where high expression strictly correlates with CD8+ T-cell exclusion and adverse clinical outcomes. Genetic ablation of tumoral CHD6 profoundly suppresses oncogene-driven HCC progression <em>in vivo</em>, a therapeutic vulnerability that is primarily dependent on an intact adaptive immune system. Mechanistically, CHD6 coordinates with HIF-1α to increase chromatin accessibility at specific promoter regions, directly driving a hypoxia-responsive, pro-angiogenic secretome. Depleting CHD6 disrupts this signaling axis, leading to structural and functional tumor vessel normalization, improved perfusion, and the reinvigoration of anti-tumor T-cell immunity. Consequently, CHD6 ablation effectively reprograms the immunosuppressive vascular ecotype, synergistically sensitizing previously refractory tumors to doxorubicin and anti-PD-L1 immune checkpoint blockade. Together, our findings uncover a novel epigenetic mechanism governing the HCC ecosystem and highlight CHD6 as a promising therapeutic target to overcome treatment resistance.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_20390640 |
| institution | Zenodo |
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| publishDate | 2026 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | CHD6 drives an immunosuppressive vascular ecotype and therapy resistance in hepatocellular carcinoma Fan, Xutong Zhang, Min <p class="MsoNormal">Aberrant tumor vasculature drives a vicious cycle of severe hypoxia and immunosuppression in hepatocellular carcinoma (HCC), creating a formidable physical and biological barrier to effective therapy. However, the upstream epigenetic master regulators dictating this pathological vascular-immune crosstalk remain largely undefined. Here, we identify the chromatin remodeler CHD6 as a critical driver of the immunosuppressive HCC microenvironment. CHD6 is significantly upregulated in human HCC, where high expression strictly correlates with CD8+ T-cell exclusion and adverse clinical outcomes. Genetic ablation of tumoral CHD6 profoundly suppresses oncogene-driven HCC progression <em>in vivo</em>, a therapeutic vulnerability that is primarily dependent on an intact adaptive immune system. Mechanistically, CHD6 coordinates with HIF-1α to increase chromatin accessibility at specific promoter regions, directly driving a hypoxia-responsive, pro-angiogenic secretome. Depleting CHD6 disrupts this signaling axis, leading to structural and functional tumor vessel normalization, improved perfusion, and the reinvigoration of anti-tumor T-cell immunity. Consequently, CHD6 ablation effectively reprograms the immunosuppressive vascular ecotype, synergistically sensitizing previously refractory tumors to doxorubicin and anti-PD-L1 immune checkpoint blockade. Together, our findings uncover a novel epigenetic mechanism governing the HCC ecosystem and highlight CHD6 as a promising therapeutic target to overcome treatment resistance.</p> |
| title | CHD6 drives an immunosuppressive vascular ecotype and therapy resistance in hepatocellular carcinoma |
| url | https://doi.org/10.5281/zenodo.20390640 |