Lipid metabolic reprogramming in NSCLC: mechanisms, microenvironment crosstalk, and therapeutic opportunities

Abnormal lipid metabolism is widely recognized as a hallmark of cancer cells. In particular, non-small cell lung cancer (NSCLC) cells exhibit heightened lipid metabolic processes to meet their biosynthetic and energetic demands, while concurrently reprogramming lipid metabolism to remodel the tumour microenvironment (TME). This review details the pivotal roles of lipid metabolic reprogramming in NSCLC. First, we delineate the distinct lipid metabolic characteristics of NSCLC, exploring their regulatory mechanisms and contributions to tumour progression. Given the significant impact of lipids on the TME, we subsequently describe the intricate crosstalk between NSCLC cells and other cellular components within the TME. Furthermore, we investigate the relationship between lipid metabolism and NSCLC treatment, encompassing its role in therapeutic resistance and the potential of targeting lipid metabolism as a therapeutic strategy. Finally, we discuss the prospects and current limitations of targeting lipid metabolism in the clinical management of NSCLC. A substantial body of evidence suggests that lipid metabolic reprogramming plays a critical role in NSCLC. Median time to progression data from a phase I clinical study demonstrated that monotherapy with the FASN inhibitor showed a preliminary signal of clinical activity in KRAS-mutant NSCLC (64% remained progression-free for > 12 weeks, n = 11) compared with KRAS-wildtype NSCLC (0% >12 weeks, n = 6; p < 0.02). However, to date, no lipid-targeted therapy has demonstrated clinically meaningful efficacy in unselected NSCLC patients. Targeting dysregulated lipid metabolism in NSCLC is supported by extensive preclinical rationale, but clinical validation remains limited to specific molecular subtypes. Realising the therapeutic potential of this strategy will require addressing fundamental gaps in target selectivity, tumour-type specificity, and clinical validation. Further studies should focus on elucidating the lipid metabolic networks in NSCLC to enhance treatment outcomes for affected patients.