TNFR2 Promotes Glycolysis to Induce PD-1 Expression Imbalance Between Effector T Cells and Tregs and Confers Immunotherapy Resistance in Cervical Cancer

Previous studies identified the PD-1 expression ratio between CD8 + effector T cells and Treg in the TME as a predictive marker for immune checkpoint blockade efficacy. Here, we confirmed that PD-1 expression on eTreg is significantly higher than on CD8 + T cells in cervical cancer, explaining the limited response to anti-PD-1 therapy. High TNFR2 expression impairs anti-PD-1 efficacy and exacerbates this PD-1 imbalance. RNA sequencing and untargeted metabolomics showed TNFR2 regulates the Warburg effect: TNFR2 downregulation reduces glucose uptake, lactate secretion, and ATP production, while glycolysis inhibition reverses TNFR2-mediated tumorigenesis in nude mouse xenografts. Lactate was identified as a key mediator of the PD-1 imbalance. Mechanistically, TNFR2 regulates tumor glycolysis via the PI3K/Akt/mTOR/c-Myc pathway, with c-Myc driving glycolytic gene expression. Inhibiting PI3K, mTOR, or c-Myc reverses TNFR2-induced glycolytic enzyme upregulation, while Akt activation restores their expression after TNFR2 downregulation. Our study identifies a novel TNFR2-PI3K/Akt/mTOR/c-Myc-glycolysis-lactate-PD-1 imbalance axis, proposing TNFR2 inhibitors enhance anti-PD-1 efficacy by reversing this imbalance. Combining TNFR2 blockade with anti-PD-1 therapy may improve cervical cancer treatment outcomes.