Abstract C103: Inhibition of MGAT1 overcomes STK11-driven immune evasion in non-small cell lung cancer

Abstract Background: Checkpoint inhibitors have emerged as a standard of care therapy for non-small cell lung cancer (NSCLC). Mutations in STK11 occur in 20% of NSCLC and are associated with poor responsiveness to anti-PD-1 agents, creating an increased need to identify novel therapeutic targets for this tumor subtype. Methods: Functional genomic screening utilizing CRISPR-Cas9 is a powerful tool to identify new therapeutic targets in cancer. We applied this technology specifically to STK11-mutant syngeneic tumor models in mice to identify targets which restore sensitivity to anti-PD-1 therapy. Results: Knockout of MGAT1, an enzyme critical for maturation of high-mannose N-glycans into hybrid and complex glycan types, was able to reverse STK11-mutant-driven resistance to anti-PD-1 treatment. Parallel in vitro screens using co-culture systems showed that disruption of N-glycosylation was also a powerful mechanism in sensitizing tumor cells to direct killing by antigen-matched CD8 T cells. Our investigation suggests that global disruption of N-glycans likely impacts the ability of T cells to recognize tumor cells. The role of MGAT1 in immune evasion was dependent on its enzymatic activity, making it a promising target for therapeutic small molecule inhibitor development. Conclusions: Our work implicates N-glycosylation as a key mediator of immune evasion in STK11 mutant NSCLC and nominates MGAT1 a novel target for therapeutic development to overcome this mechanism. Citation Format: Kiera M. Vassallo, Yingnan Chen, Katarzyna B. Handing, Alvin Lu, Samuel Meier, Shangtao Liu, Binzhang Shen, Teng Teng, Yi Yu, Alan Huang, Chengyin Min, Brian Haines, William Mallender, Sining Sun, Jannik Andersen, Wenhai Zhang, Serge Gueroussov. Inhibition of MGAT1 overcomes STK11-driven immune evasion in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C103.