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

Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy that frequently shows limited responses to chemotherapy and immune checkpoint blockade. Such therapeutic resistance is partly attributed to the persistence of cancer stem-like cells (CSCs) and the establishment of an immune-cold tumor microenvironment. However, the upstream regulators that orchestrate these malignant traits remain incompletely understood. Here, I identify dysadherin as a previously unrecognized upstream activator of YAP that drives CSC plasticity and immune evasion via the FAK/YAP/TEAD2 signaling axis. Through single-cell transcriptomic profiling, in vitro functional assays, and multiple in vivo models—including a humanized immune mouse system—I demonstrate that dysadherin induces pluripotency-associated programs such as OCT and increases PD-L1 expression. These alterations promote stem-like tumor behavior and are associated with T-cell exclusion. Importantly, either genetic silencing of dysadherin or peptide-based pharmacologic inhibition reactivates anti-tumor immunity and enhances therapeutic sensitivity. Together, these results reveal a mechanistic connection between dysadherin- dependent adhesion signaling and the transcriptional control of stemness and immune escape. Collectively, this work establishes the dysadherin–YAP axis as a central driver of HCC progression and treatment resistance, and supports its potential as a therapeutic target in advanced liver cancer.