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

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 synergistic anti-tumor effect with PD-1 antibodies using MC38 tumor-bearing mouse model. Compared with monotherapy, combined therapy of PFD and PD-1 antibodies caused a pronounced improvement in anti-tumor immune responses by boosting the infiltration of both CD8+ and CD4+ T cells, with an excellent biosafety. Thus, our findings offer compelling evidence to support the anti-tumor and immunomodulatory roles of PFD in CRC, highlighting the potential of repurposing PFD in improving anti-tumor response to immune checkpoint blockades (ICBs).