In non-viral HCC, the STRIDE regimen (single priming dose tremelimumab plus durvalumab) was the only regimen to significantly improve OS (HR = 0.75, 0.59-0.96).<h4>Conclusions</h4>For first-line therapy in advanced HCC, ICI-based combinations with anti-VEGF/anti-angiogenic agents generally outperform sorafenib, with discernible etiology-specific optima: HBV-related HCC favors sintilimab plus bevacizumab biosimilar or atezolizumab plus bevacizumab; HCV-related HCC favors atezolizumab plus bevacizumab; and in non-viral disease, STRIDE demonstrates a unique OS advantage. Here, VEGFA is linked to viral infectious disease.