Critical reviews in oncology/hematology · 2026
Amino acid metabolic reprogramming in immunotherapy for hepatocellular carcinoma: Adaptive resistance, patient stratification, and longitudinal monitoring.
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He Hongyang, Qiao Zhiheng, Gai Xiaocan, Ji Guoliang, Liu Shumin
Аннотация
BACKGROUND: Immunotherapy has become an important component of systemic treatment for advanced hepatocellular carcinoma (HCC), yet durable benefit remains limited to a subset of patients because of marked response heterogeneity and acquired resistance.
PROBLEM: Current biomarkers are often static, single-time-point indicators that incompletely capture evolving tumor-immune metabolic interactions before and during therapy. In HCC, amino acid availability, nitrogen handling, and suppressive metabolite production are shaped by tumor-intrinsic programs, immune-cell competition, and liver-specific metabolic physiology.
MAIN BODY: This review frames amino acid metabolic reprogramming as a mechanistically and translationally informative axis for HCC immunotherapy. We discuss three clinically relevant domains. First, pretreatment amino acid states may inform patient stratification by reflecting nutrient competition, immune readiness, and transcriptomic signatures linked to glutamine, tryptophan-kynurenine, lysine, and arginine/nitrogen metabolism. Second, adaptive resistance is highlighted as the domain with the strongest mechanistic support, in which therapy pressure rewires amino acid transport, catabolism, and cross-compartment metabolic exchange to create immunosuppressive niches, reinforce suppressive myeloid and regulatory T-cell states, and impair effector T-cell function. Third, longitudinal monitoring through circulating metabolites, paired tissue profiling, spatial multi-omics, and computational integration is evaluated according to mechanistic resolution and clinical scalability.
CONCLUSION: Amino acid metabolism should be viewed not merely as a descriptive hallmark, but as a clinically organizing and potentially actionable framework for organizing patient stratification, adaptive resistance, and longitudinal monitoring in HCC immunotherapy. Prioritizing reproducible, actionable on-treatment resistance states may help move the field beyond static biomarkers toward earlier therapeutic adaptation.
PROBLEM: Current biomarkers are often static, single-time-point indicators that incompletely capture evolving tumor-immune metabolic interactions before and during therapy. In HCC, amino acid availability, nitrogen handling, and suppressive metabolite production are shaped by tumor-intrinsic programs, immune-cell competition, and liver-specific metabolic physiology.
MAIN BODY: This review frames amino acid metabolic reprogramming as a mechanistically and translationally informative axis for HCC immunotherapy. We discuss three clinically relevant domains. First, pretreatment amino acid states may inform patient stratification by reflecting nutrient competition, immune readiness, and transcriptomic signatures linked to glutamine, tryptophan-kynurenine, lysine, and arginine/nitrogen metabolism. Second, adaptive resistance is highlighted as the domain with the strongest mechanistic support, in which therapy pressure rewires amino acid transport, catabolism, and cross-compartment metabolic exchange to create immunosuppressive niches, reinforce suppressive myeloid and regulatory T-cell states, and impair effector T-cell function. Third, longitudinal monitoring through circulating metabolites, paired tissue profiling, spatial multi-omics, and computational integration is evaluated according to mechanistic resolution and clinical scalability.
CONCLUSION: Amino acid metabolism should be viewed not merely as a descriptive hallmark, but as a clinically organizing and potentially actionable framework for organizing patient stratification, adaptive resistance, and longitudinal monitoring in HCC immunotherapy. Prioritizing reproducible, actionable on-treatment resistance states may help move the field beyond static biomarkers toward earlier therapeutic adaptation.