CMTM6 promotes radioresistance in hepatocellular carcinoma via EMT induction and synergistic interaction with VEGFA

Radiotherapy is a cornerstone treatment for hepatocellular carcinoma (HCC), yet its efficacy is often compromised by radioresistance. This study identifies the CMTM6-VEGFA axis as a pivotal driver of resistance. We report that HCC cells with acquired radioresistance exhibit upregulated CMTM6 expression, enhanced epithelial-mesenchymal transition (EMT), and increased invasive potential. Functionally, CMTM6 overexpression confers radioresistance, whereas CMTM6 knockdown sensitizes HCC cells to irradiation. Mechanistically, we demonstrate a physical interaction between CMTM6 and VEGFA. These two proteins act synergistically to promote EMT and radioresistance, which is effectively reversed upon VEGFA knockdown. This reversal is associated with inactivation of the AKT/mTOR pathway and a shift in EMT marker expression. Clinical analysis of 90 HCC samples reveals significant co-upregulation of CMTM6 and VEGFA in tumor tissues, with the highest levels observed in the prognostically unfavorable macrotrabecular-massive (MTM-HCC) subtype. Importantly, high co-expression of CMTM6 and VEGFA is strongly correlated with poor overall survival in patients. Our findings identify a novel CMTM6-VEGFA signaling axis that promotes radioresistance in HCC through EMT induction, establishing this pathway as a promising therapeutic target for overcoming treatment resistance, particularly in aggressive MTM-HCC.