Radiation potentiates natural killer cell therapy combined with Atezolizumab and Bevacizumab in SNU-398 hepatocellular carcinoma models

Hepatocellular carcinoma (HCC) frequently exhibits an immunosuppressive tumor microenvironment. We evaluated whether radiation-induced tumor-cell phenotypic changes could support primary natural killer (NK) cell therapy combined with atezolizumab plus bevacizumab (Ate/Bev). Three HCC cell lines (SNU-398, PLC/PRF/5, and Huh7) were irradiated with 5 or 10 Gy and analyzed for immune-related surface markers and functional NK cell cytotoxicity, together with two xenograft experiments were performed using SNU-398. Radiation increased several NK cell-recognition ligands across all three cell lines, although the magnitude, kinetics, and PD-L1 response were cell-line dependent. In SNU-398, radiation plus Ate/Bev pretreatment increased NK cell-mediated lysis compared with the nonirradiated and Ate/Bev-only conditions. In established, advanced-stage xenografts, IR + NK + Ate/Bev produced the greatest tumor-growth inhibition among the tested groups and outperformed NK + Ate/Bev without irradiation. In contrast, in a separate low-burden, early-stage model, NK + Ate/Bev alone was sufficient to suppress tumor growth without irradiation. Together, these findings suggest that the multimodal combination of radiotherapy (RT), Ate/Bev, and NK cell therapy may represent a potential strategy to help address tumor immune evasion within the tested model, with RT contributing most to efficacy against advanced-stage disease and the NK + Ate/Bev backbone retaining activity even without irradiation in early-stage disease.