High-dose Vitamin C inhibits PD-L1 expression by activating AMPK in colorectal cancer

Vitamin C (VitC) has elicited considerable interest regarding its potential role in cancer therapy; however, its effects on tumor immunity remain unclear. In colorectal cancer (CRC), although anti-PD-1/PD-L1 therapies demonstrate promise, their efficacy is still constrained. Our prior research demonstrated that VitC can inhibit tumor growth by suppressing the Warburg effect. This study aims to explore the effects of high-dose VitC on PD-L1 expression in CRC, focusing on its underlying mechanisms and potential for enhancing immunotherapy. We found that VitC inhibits aerobic glycolysis in HCT116 cells while also downregulating PD-L1 expression. Further investigations indicated that this process is mediated by VitC's activation of AMPK, which downregulates HK2 and NF-κB, ultimately resulting in reduced PD-L1 expression and increased T cell infiltration. Notably, we observed that VitC and the PD-L1 monoclonal antibody atezolizumab exhibit comparable tumor-inhibiting abilities, and their combined use further enhances this efficacy. In conclusion, our results demonstrate that high-dose VitC activates AMPK, downregulates PD-L1 expression, mitigates immune evasion, and suppresses tumor growth. This provides a promising strategy for optimizing immunotherapy in CRC.