RAD18 facilitates cancer progression and immunosuppression via the AKT/mTOR/c-Myc axis: a multi-omics analysis

RAD18, a key E3 ubiquitin ligase implicated in DNA repair and genome stability, is tightly linked to cancer malignant progression, yet its pan-cancer prognostic and immunotherapeutic value remains poorly defined. Herein, we performed a comprehensive pan-cancer multi-omics analysis and validated the oncogenic mechanisms of RAD18 in liver hepatocellular carcinoma, pancreatic adenocarcinoma and triple-negative breast cancer via in vitro and in vivo assays. RAD18 was significantly overexpressed in 22 cancer types, associated with gene mutation, hypomethylation, poor prognosis and favorable diagnostic efficacy, serving as an independent poor prognostic factor for multiple cancers. Mechanistically, RAD18 promoted tumor proliferation, migration and immunosuppressive microenvironment remodeling by activating the AKT/mTOR/c-Myc axis and regulating TGF-β1/PD-L1 expression. Moreover, low RAD18 expression predicted a favorable response to immune checkpoint blockade therapy, while its high expression correlated with anti-PD-1 resistance in triple-negative breast cancer. Collectively, our findings identify RAD18 as a potential pan-cancer prognostic biomarker and immunotherapeutic target, with targeting RAD18 holding promise for reversing immunotherapy resistance in solid tumors.