KSR2 functions as a metabolic checkpoint for anti-PD-1 resistance by reprogramming glucose metabolism.

Immune checkpoint blockade targeting the PD-1/PD-L1 axis has revolutionized cancer therapy, yet the frequent emergence of resistance limits its clinical efficacy. Elucidating the mechanisms underlying resistance and developing effective strategies remain critical challenges in tumor immunotherapy. This study identifies kinase suppressor of Ras 2 (KSR2) as a driver of resistance to anti-PD-1 therapy in lung cancer. Transcriptomic analysis of an anti-PD-1-resistant mouse model and public clinical datasets revealed upregulation of KSR2 in resistant tumors. In vivo functional studies demonstrated that KSR2 overexpression is sufficient to confer resistance, while its knockdown resensitizes tumors to PD-1 blockade. Mechanistically, KSR2 functions as a central metabolic checkpoint, driving profound glucose metabolic reprogramming in cancer cells by enhancing glucose uptake, potentiating the Warburg effect, promoting lactate accumulation, and disrupting the tricarboxylic acid cycle. This metabolic reprogramming was subsequently associated with an immunosuppressive tumor microenvironment, characterized by reduced infiltration and impaired function of CD8⁺ T cells, alongside an enrichment of regulatory T cells. These findings suggest that KSR2 plays a role in modulating immunotherapy response, indicating a potential link between tumor metabolism and immune evasion. KSR2 emerges as a candidate target for further exploration in overcoming anti-PD-1 resistance.