CHD6 drives an immunosuppressive vascular ecotype and therapy resistance in hepatocellular carcinoma

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 in vivo, 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.