Therapeutic strategies of metabolic reprogramming in non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) remains a leading cause of cancer-related mortality worldwide, with existing therapies frequently hindered by drug resistance and immunosuppression. Metabolic reprogramming (glycolysis, lipid metabolism, and amino acid metabolism) has emerged as a core hallmark driving NSCLC progression, tumor microenvironment (TME) remodeling, and treatment failure, transcending the classical Warburg effect to involve intricate cross-talk between cancer cells and stromal components.

This review systematically synthesizes the latest insights into the regulatory mechanisms of metabolic reprogramming in NSCLC, highlighting how dysregulated glycolytic flux, altered lipid synthesis/oxidation, and adaptive amino acid utilization collectively sustain tumor growth, invasion, and immune escape. We critically examine the interplay between metabolic reprogramming and driver gene mutations (EGFR/KRAS/ALK), unraveling how mutation-specific metabolic adaptations contribute to targeted therapy resistance, and explore the role of metabolic heterogeneity in shaping treatment responses. Furthermore, we dissect actionable therapeutic strategies that target metabolic vulnerabilities, including immunotherapy synergies (e.g. PD-1 inhibitors combined with PKM2/ferroptosis targeting, metabolically modified CAR-T cells), subtype-specific targeted interventions (e.g. DPP4/GFPT2/PFKFB3 inhibitors reversing mutation-driven metabolic resistance), and chemotherapy sensitization approaches (e.g. CPT1A/GLUD1 inhibitors overcoming cisplatin resistance via suppressing metabolic compensation).

This review underscores the clinical potential of targeting metabolic reprogramming to address unmet therapeutic needs, proposing synergistic regimens and personalized metabolic therapy frameworks that hold promise for improving NSCLC patient outcomes.