PER2 knockdown drives immunotherapy resistance in gastric cancer via metabolic reprogramming of myeloid-derived suppressor cells.

Circadian rhythm disruption is increasingly linked to tumor progression and therapy resistance, but its role in immune evasion remains unclear. Here, we demonstrate that knockdown of the core circadian gene PER2 (PER2-KD) drives resistance to immune checkpoint inhibitors (ICIs) in gastric cancer (GC) by promoting monocytic myeloid-derived suppressor cell (M-MDSC) accumulation and metabolic reprogramming. RNA-seq and scRNA-seq revealed that PER2-KD upregulates immunosuppressive genes (e.g., PD-L1, IL-10) while suppressing T cell activation signals. Mechanistically, PER2-KD GC cells secrete elevated VEGF and IL-6, inducing STAT3 phosphorylation in M-MDSCs and enhancing their immunosuppressive function. Untargeted metabolomics identified glycolysis and fatty acid metabolism as key pathways dysregulated in PER2-KD M-MDSCs, with lactate accumulation further amplifying CD8 + T cell dysfunction. In vivo, PER2-KD tumors exhibited accelerated growth, reduced PD-1 blockade efficacy, and shorter survival, accompanied by increased M-MDSC infiltration and lactate levels. Neutralizing VEGF/IL-6 or inhibiting lactate metabolism restored CD8+ T cell activity, suggesting actionable therapeutic targets. Our study unveils PER2-KD as a novel regulator of metabolic-immune crosstalk in GC, providing a mechanistic basis for ICI resistance and highlighting circadian-metabolic interventions to improve immunotherapy outcomes.