Immune Metabolic Checkpoints in Sepsis: From Metabolic Reprogramming to Metabolic Phenotype-Driven Diagnostic and Therapeutic Strategies

The immune status during sepsis is highly heterogeneous: hyperinflammation and immune paralysis may occur sequentially, concurrently, or in overlapping phases. Current therapeutic strategies based solely on anti-inflammatory or immune-enhancing approaches have shown limited success. Recent evidence has linked immune cell polarization to distinct metabolic patterns. Therefore, we outline the concept of immune metabolic checkpoints, which are molecular nodes characterized by substantial differences in metabolic flux between pro-inflammatory and anti-inflammatory immune cells. Their associated metabolites can be detected in peripheral blood, and pharmacological interventions targeting these checkpoints can modulate immune cell phenotypes. We review three core pathways: the succinate-itaconate axis, the lactate-pyruvate axis, and the acylcarnitine spectrum associated with fatty acid oxidation and the metabolic adaptability of immune-suppressive cells. We further propose a metabolic phenotype classification framework for sepsis based on the succinate-to-itaconate, lactate-to-pyruvate, and lactylation-to-acetylation ratios together with the acylcarnitine spectrum and define three metabolic subtypes, hypermetabolic, tolerance, and failure, corresponding respectively to the cytokine storm, immune paralysis, and irreversible organ failure phases of sepsis. Finally, we discuss therapeutic strategies targeting immune metabolic checkpoints and the challenges associated with their clinical translation. Integrating immune metabolic checkpoints may provide new opportunities for the precise classification and individualized treatment of sepsis.