Penfluridol enhances anti-tumor immunity in colorectal cancer by inducing proteasome-mediated degradation of PD-L1 via the activation of AMPK.

ABSTRACT: Colorectal cancer (CRC) is a prevalent and aggressive malignancy globally, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have become one of the effective strategies for the treatment of this disease. Here, we discovered penfluridol (PFD), an antipsychotic drug, as a novel modulator of this immune checkpoint pathway. Firstly, we confirmed anti-tumor efficacy of PFD in CRC cells by a series of in vitro experiments. Next, we found that PFD promoted the ubiquitin-proteasome-mediated degradation of PD-L1 to reduce PD-L1 expression on cell surface, thereby enhancing the killing effect of T cells on cancer cells. Further mechanistic investigations revealed that PFD activated AMP-activated protein kinase (AMPK) to facilitate PD-L1 degradation. Also, we demonstrated that PFD had a

SUBMITTER: Wang J 

PROVIDER: S-EPMC12529539 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature