Abstract
Early identification of unresectable hepatocellular carcinoma (HCC) patients who may benefit from immune checkpoint inhibitors (ICIs) is crucial for optimizing outcomes. Here, we developed a multimodal fusion (MMF) system integrating CT-derived deep learning features and clinical data to predict overall survival (OS) and progression-free survival (PFS). Using retrospective multicenter data (n = 859), the MMF combining an ensemble deep learning (Ensemble-DL) model with clinical variables achieved strong external validation performance (C-index: OS = 0.74, PFS = 0.69), outperforming radiomics (29.8% OS improvement), mRECIST (27.6% OS improvement), clinical benchmarks (C-index: OS = 0.67, p = 0.0011; PFS = 0.65, p = 0.033), and Ensemble-DL (C-index: OS = 0.69, p = 0.0028; PFS = 0.66, p = 0.044). The MMF system effectively stratified patients across clinical subgroups and demonstrated interpretability through activation maps and radiomic correlations. Differential gene expression analysis revealed enrichment of the PI3K/Akt pathway in patients identified by the MMF system. The MMF system provides an interpretable, clinically applicable approach to guide personalized ICI treatment in unresectable HCC.