An integrated pathway mutation and clinical model predicts survival in unresectable HCC with hepatic arterial infusion chemotherapy combined with lenvatinib and tislelizumab.
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BACKGROUND: Triple combination therapy consisting of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and tislelizumab has shown encouraging clinical efficacy in patients with advanced hepatocellular carcinoma (HCC). However, robust prognostic models to predict treatment outcomes remain lacking. METHODS: A total of 83 patients with unresectable HCC receiving HAIC combined with lenvatinib and tislelizumab were enrolled to develop a prognostic prediction model, which was subsequently validated in an independent cohort of 26 patients. Underlying mechanisms were investigated using targeted exome sequencing and RNA sequencing. RESULTS: We assessed the cumulative impact of gene mutations and identified three signaling pathways associated with progression-free survival (PFS), namely the Hedgehog, ErbB, and focal adhesion pathways, in patients undergoing triple combination therapy. An integrated prognostic model incorporating these PFS-related pathways and key clinical risk factors-aspartate aminotransferase, Child-Pugh class, and presence of metastasis-was established and validated. Mechanistic analyses demonstrated enrichment of angiogenesis- and hypoxia-related signatures, along with increased immune cell infiltration in responders, providing a biological basis for the observed therapeutic efficacy. CONCLUSION: This integrated prognostic model, combining pathway-level genomic alterations with clinical risk factors, enables reliable prediction of treatment outcomes in patients with unresectable HCC receiving HAIC, lenvatinib, and tislelizumab. It may serve as a valuable tool for guiding personalized therapeutic decision-making.