CD36-Mediated Fatty Acid Oxidation in CTCs Drives Immune Evasion and Metastasis in NSCLC.

[BACKGROUND] Immune checkpoint inhibitors (ICIs) show clinical benefit in subsets of non-small cell lung cancer (NSCLC) patients, yet resistance remains a major challenge. Circulating tumor cells (CTCs) contribute to tumor dissemination and immune regulation. This study investigated the metabolic features of CTC subpopulations under PD-1 resistance, with a focus on the role of CD36CTCs in immune evasion and pre-metastatic niche (PMN) formation.

[METHODS] PD-1-resistant in vitro and murine NSCLC models were established to enrich and isolate CTCs. CD36 CTCs were characterized using lipid metabolomics, RNA sequencing, and functional assays. Their roles in PMN formation and immune suppression were evaluated using lung metastasis models and a tri-cell co-culture system. Fatty acid oxidation (FAO) dependency was assessed by lipid imaging, mitochondrial activity analysis, and pharmacological inhibition with etomoxir.

[RESULTS] CD36 CTCs were enriched under PD-1 resistance and exhibited enhanced lipid accumulation, increased mitochondrial activity, and FAO dependency. Multi-omics analyses revealed activation of lipid metabolic pathways associated with immune suppression and extracellular matrix remodeling. Functionally, CD36 CTCs promoted PMN formation and inhibited T-cell activation, while FAO inhibition significantly reduced their migratory and metastatic potential.

[CONCLUSION] CD36 CTCs drive immune evasion and metastasis in PD-1-resistant NSCLC through FAO-dependent metabolic reprogramming. Targeting this metabolic vulnerability may enhance the efficacy of immunotherapy.