FAD Subtype-Guided Combination Therapy for Unresectable Hepatocellular Carcinoma

This prospective, multicenter Phase II study evaluates a precision-medicine treatment strategy for unresectable hepatocellular carcinoma (HCC) using a metabolic classification system based on fatty acid degradation (FAD). Prior translational research has shown that HCC exhibits heterogeneous metabolic phenotypes, and that tumors with distinct FAD signatures demonstrate different immune microenvironments and therapeutic sensitivities. Building on these findings, this study applies FAD subtype profiling in clinical practice to guide individualized treatment selection. All enrolled patients will undergo tumor tissue analysis for transcriptomic assessment and FAD scoring. When tumor tissue is not immediately obtainable, MRI fat-fraction measurement may be used temporarily to facilitate enrollment, with tissue-based classification performed afterward. Based on the predefined FAD subtypes (F1, F2, and F3), patients will be allocated to tailored therapeutic strategies designed to align with each subtype's metabolic and microenvironmental characteristics. Patients with F1 or F2 subtypes will receive systemic therapy with camrelizumab and apatinib, reflecting prior evidence that these subtypes may benefit from immunotherapy combined with anti-angiogenic therapy. Patients with the F3 subtype that characterized by enhanced lipid metabolic activity will receive TACE in addition to camrelizumab and apatinib. Treatment is delivered in 3-week cycles, with imaging assessments performed regularly to evaluate tumor response. Safety will be closely monitored throughout the study, including immunotherapy-related toxicities, anti-angiogenic drug-associated events, and TACE-related complications. After discontinuation of study treatment, participants will enter a structured follow-up schedule to monitor survival and subsequent treatments. In addition to evaluating clinical outcomes, the study incorporates exploratory biomarker analyses, including transcriptomics, metabolomics, and imaging-based fat quantification. These analyses aim to improve understanding of how metabolic subtypes influence therapeutic response and resistance mechanisms, and to assess whether MRI-based fat fraction can serve as a noninvasive surrogate for molecular FAD classification. Overall, this study seeks to translate metabolic phenotyping into clinical decision-making and to determine whether FAD-guided personalized therapy can improve treatment outcomes for patients with unresectable HCC.