YTHDF1 boosts the lactate accumulation to potentiate cervical cancer cells immune escape

Lactate is a major metabolic product of tumor cells in microenvironment. Increasing evidence has indicated that lactate accumulation could alter the immune response in human cancers, including cervical cancer. However, the function and significance of N⁶-methyladenosine (m⁶A) reader YTHDF1 in cervical cancer cells' lactate metabolism and immunotherapy remain obscure. Results illustrated that YTHDF1 predicted unfavorable clinical outcomes of cervical cancer, which was negatively correlated with CD8⁺ T cell infiltration. In the co-culture of tumor cells with CD8⁺ T cells, YTHDF1 overexpression promoted the lactate accumulation and attenuated the cytotoxic CD8⁺ T cell's killing effect. Correspondingly, YTHDF1 knockdown exerted the opposite effects. Mechanistically, YTHDF1 targeted the m⁶A site on SLC16A1 gene (MCT1) to determine its fate. YTHDF1 upregulated MCT1 expression by enhancing MCT1 stability mediated by m⁶A-modified manner. Collectively, our results revealed an oncogenic role played by YTHDF1 in cervical cancer through m⁶A/MCT1-dependent manner. In conclusion, these findings unveil the immune escape-promoting effect of YTHDF1 in cervical cancer by boosting the lactate accumulation, which might illuminate a novel target for more precise immunotherapy.