GFPT2 controls immune evasion in EGFR-mutated non-small cell lung cancer

Abstract In the evolving field of cancer immunotherapy, EGFR-mutated non-small cell lung cancer (NSCLC) poses a significant obstacle due to its inherent resistance to conventional treatments. The development of an effective strategy to overcome this resistance remains a challenge. Here we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a prime architect in the immune evasion phenotype induced by EGFR mutations. Mechanistically, in the presence of EGFR mutations, the expression of GFPT2, typically low in normal tissues, is significantly upregulated via the EGFR/IRE1α/Xbp1s signaling pathway. This results in a significant increase in intracellular UDP-GlcNAc levels, altering N-glycosylation profiles extensively. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and also amplifies CD73 glycosylation to intensify adenosine-mediated suppression of CD8+T cells. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 also hinders the infiltration of CD8+T cells into tumors by regulating EGFR glycosylation and subsequent secretion of CXCL10 and VEGF. The validation of this GFPT2-mediated immune evasion phenotype is substantiated by compelling clinical evidence. We further identified a GFPT2 isoform-specific inhibitor that can enhance the efficacy of PD-1 blockade therapy beyond current strategies, as evidenced by results in xenograft models and patient-derived organoids. Taken together, our results highlight the potential of GFPT2 as a metabolic checkpoint in controlling immune escape in EGFR-mutated NSCLC, offering an innovative and druggable target to bolster immunotherapy outcomes in NSCLC with EGFR mutations.