Enhanced peripheral blood mononuclear cell lipid metabolism drives poor immunotherapy response via ferroptotic stress‐induced T cell exhaustion in hepatocellular carcinoma

Abstract Resistance to immunotherapy remains a central challenge in advanced hepatocellular carcinoma (HCC). The role of systemic factors, particularly the metabolic fitness of the circulating immune reservoir, in driving this resistance remains poorly understood. This study aimed to identify pre‐treatment metabolic signatures in peripheral blood mononuclear cells (PBMCs) that predict therapeutic response and to elucidate the underlying mechanisms of T‐cell dysfunction. We performed integrated multi‐omics analyses, including proteomics, metabolomics, lipidomics, and phosphoproteomics, on pre‐treatment PBMCs from a cohort of HCC patients receiving anti‐PD‐1 immunotherapy‐based combination treatment. Predictive metabolic signatures were identified, and key mechanisms were validated using flow cytometry, confocal microscopy, and molecular analyses. An enhanced lipid metabolic signature in pre‐treatment PBMCs was identified as a powerful and independent predictor of poor immunotherapy response and survival. We found that a lipid‐enriched plasma milieu in non‐responders imposes a metabolic constraint on PBMCs. Specifically, CD36 upregulation correlates with increased lipid uptake and accumulation of glycerophospholipids and sphingolipids, triggering sub‐lethal ferroptotic stress (characterized by ferroptosis molecular hallmarks and functional impairment in viable cells without overt cell death) and subsequent T cell exhaustion. This ferroptotic stress state exhibited lipid peroxidation, reduced GPX4 expression, and elevated intracellular iron (Fe 2+ ), and was mechanistically sustained by suppressed AKT survival signaling coupled with hyperactive inflammatory pathways (MAPK, NF‐κB). Importantly, this metabolic dysfunction was reversible upon blocking lipid peroxidation. The systemic metabolic fitness of circulating PBMCs is an important determinant of immunotherapy efficacy in HCC that complements tumor‐intrinsic factors. Our findings provide a new framework for developing non‐invasive predictive biomarkers and demonstrate that PBMC ferroptotic stress is mechanistically reversible, providing a rationale for evaluating systemic metabolic modulation as a strategy to enhance immunotherapy outcomes.