Background <p>Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, responsible for roughly 85% of cases and a significant portion of cancer-related deaths globally. Despite advances in early detection and treatment, NSCLC remains a clinically challenging disease due to factors like late-stage diagnosis, tumor heterogeneity, and resistance to therapy. Recent research has increasingly focused on the role of altered cancer metabolism, particularly pathways like glycolysis, glutaminolysis, and lipid metabolism, which enable NSCLC cells to thrive under adverse conditions and evade treatment.</p> Purpose <p>This review aims to explore the unique metabolic reprogramming in NSCLC, examining how alterations in key metabolic pathways contribute to tumor growth, metastasis, and therapeutic resistance. Understanding these metabolic changes may uncover new therapeutic opportunities and strategies to overcome resistance mechanisms.</p> Main body <p>NSCLC metabolism is characterized by metabolic heterogeneity with varying dependencies on aerobic glycolysis (Warburg effect), oxidative phosphorylation (OXPHOS), glutamine addiction, and lipid synthesis. Cancer cells exhibit remarkable metabolic plasticity to adapt to environmental stresses such as hypoxia and nutrient deprivation. Oncogenic mutations, such as those in KRAS, EGFR, TP53, LKB1, and KEAP1, drive these alterations through distinct mechanisms affecting glucose metabolism, mitochondrial function, redox homeostasis, and nutrient sensing. The tumor microenvironment (TME) plays a critical role, with metabolic crosstalk between cancer cells and immune cells, cancer-associated fibroblasts (CAFs), and exosomes. Emerging therapeutic strategies aim to target glycolysis, glutaminolysis, lipid metabolism, mitochondrial function, and ferroptosis pathways, either alone or in combination with immune checkpoint inhibitors or chemotherapies. However, clinical translation faces significant challenges including off-target toxicity, limited efficacy, lack of predictive biomarkers, and emergence of adaptive resistance mechanisms.</p> Conclusion <p>The metabolic reprogramming in NSCLC presents both challenges and opportunities for therapeutic intervention. While targeting metabolic vulnerabilities holds promise, success requires addressing tumor metabolic heterogeneity, adaptive plasticity, and TME interactions. Integration of advanced technologies including single-cell multi-omics, AI-driven metabolic mapping, and hyperpolarized MRI offers new opportunities for patient stratification and personalized treatment. Overcoming clinical trial failures necessitates better understanding of resistance mechanisms, development of metabolic biomarkers, and optimization of combination strategies.</p> Graphical Abstract <p>Comprehensive overview of metabolic reprogramming in NSCLC showing the interplay between major metabolic pathways (glycolysis, glutaminolysis, lipid metabolism, and OXPHOS), oncogenic drivers (KRAS, EGFR, TP53, LKB1, KEAP1), tumor microenvironment interactions (hypoxia, immune cells, CAFs), and therapeutic targeting strategies. The schematic illustrates how cancer cells utilize multiple metabolic pathways simultaneously, with metabolic plasticity enabling adaptation to environmental stress and therapy. Key resistance mechanisms including pathway switching, tumor heterogeneity, and TME support are highlighted. Therapeutic interventions targeting specific metabolic nodes are indicated, along with combination strategies involving immunotherapy. The abstract emphasizes the complexity of metabolic networks and the need for multi-targeted approaches to overcome therapeutic resistance.&#xa0;•</p> <p></p>