Metabolic Reprogramming in Lung Cancer: Hallmarks, Mechanisms, and Targeted Strategies to Overcome Immune Resistance

Lung cancer remains the leading cause of cancer-related mortality worldwide. Although immunotherapy has revolutionized lung cancer treatment, its efficacy is often hindered by primary and acquired immune resistance. Increasing evidence indicates that metabolic reprogramming plays a crucial role in tumor progression and the establishment of an immunosuppressive tumor microenvironment in both non-small cell lung cancer and small cell lung cancer.

This review comprehensively summarizes recent preclinical and clinical findings on the metabolic alterations associated with immune suppression in lung cancer. The major metabolic pathways-glycolysis, lipid metabolism, and amino acid metabolism-were systematically analyzed, focusing on their regulatory enzymes, signaling pathways, and interactions with immune responses.

Metabolic reprogramming profoundly influences tumor-immune interactions. Enhanced glycolysis, dysregulated lipid synthesis and oxidation, and altered amino acid metabolism collectively contribute to immune evasion by impairing T-cell activation, promoting regulatory immune cell populations, and modulating cytokine and checkpoint molecule expression.

Targeting tumor metabolic remodeling offers a promising strategy to overcome immune resistance and improve the therapeutic efficacy of immunotherapy in lung cancer. Continued efforts to elucidate the molecular mechanisms linking metabolism and immunity may pave the way for novel combination therapies with durable clinical benefits.