Metabolism-guided precision oncology in hepatocellular carcinoma: vascular, stromal and immune crosstalk

Hepatocellular carcinoma (HCC) is characterized by extensive metabolic reprogramming, aberrant angiogenesis, immune evasion, and frequent resistance to systemic therapy. This review aims to synthesize current evidence on tumor-stroma-vascular metabolic crosstalk in HCC and to evaluate how this biology may inform metabolism-guided precision oncology. We highlight lactate and lysine lactylation (Kla) as a central metabolic–epigenetic axis linking glycolytic flux to pro-angiogenic transcription, endothelial activation, macrophage polarization, stromal remodeling, metastasis, and therapeutic resistance. We further discuss how major molecular contexts, including CTNNB1 -mutant/GLUL-high, TP53 -mutant high-glycolytic, and MYC/AKT-driven proliferative tumors, may exhibit distinct metabolic–angiogenic dependencies. Candidate biomarkers, including MCT4 and context-dependent MCT1 expression, OXCT1, lactylation marks, CAF and TAM subsets, circulating metabolites, metabolic imaging, and spatial biopsy readouts, are evaluated according to their biological rationale, assay feasibility, evidence level, and translational limitations. We also critically appraise investigational therapeutic strategies targeting lactate transport, glycolysis, HIF signaling, stromal metabolism, and vascular–immune–metabolic interactions. Overall, metabolism-guided precision oncology in HCC remains an emerging framework rather than an established clinical algorithm. Future biomarker-enriched trials integrating molecular profiling, spatial diagnostics, circulating metabolic monitoring, and predefined pharmacodynamic endpoints will be required to translate metabolic–vascular biology into clinically actionable patient stratification.