Dysadherin/YAP axis fuels stem plasticity and immune escape in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy that is often refractory to chemotherapy and immune checkpoint inhibitors. This therapeutic resistance is driven in part by the persistence of cancer stem-like cells (CSCs) and the development of an immune-cold tumor microenvironment. However, the upstream regulators that coordinate these malignant features remain poorly defined. In this study, we identified dysadherin as a novel upstream activator of YAP that promotes both CSC plasticity and immune evasion through the FAK/YAP/TEAD2 signaling axis. Using single-cell transcriptomic analysis, in vitro assays, and multiple in vivo models including a humanized immune mouse system, we showed that dysadherin enhances the expression of pluripotency genes, such as OCT4 and upregulates PD-L1. These changes support stem-like tumor behavior and contribute to T-cell exclusion, fostering an immunosuppressive niche. Notably, genetic knockdown or peptide-based pharmacologic inhibition of dysadherin effectively restored antitumor immune activation, suppressed metastasis and improved therapeutic responsiveness. Our findings reveal a mechanistic link between dysadherin-mediated cell adhesion signaling and the transcriptional regulation of both stemness and immune escape. Collectively, these findings establish the dysadherin/YAP axis as a key driver of HCC progression and resistance, and highlight it as a compelling therapeutic target that could overcome treatment failure in advanced liver cancer.