<i>DNASE1L3</i> overexpression similarly restricted organoid growth and suppressed pathway activity.<h4>Conclusion</h4><i>DNASE1L3</i> acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression, thereby influencing both tumor cell behavior and macrophage-mediated immune responses. Here, CD274 is linked to neoplasm.