Cepharanthine-mediated PD-L1 autophagic degradation via regulation of TSPO and RILP boosts anti-lung cancer chemo-immunotherapy efficacy.

Non-small cell lung cancer (NSCLC) accounts for the second highest incidence and highest mortality rates globally, wherein immune checkpoint molecules such as PD-L1, highly-expressed in malignant cells bind to PD-1 located in immunocytes, leading to immune escape. We hereby investigate the role of phytomedicine Cepharanthine (CEP) in the regulation of PD-L1 in NSCLC and elucidate the involved mechanism. CEP showed robust cytotoxicity against lung cancer cells, as demonstrated by reduced cell viability and elevated apoptosis. Furthermore, the tumor grafts in mice were significantly suppressed by CEP. Importantly, CEP down-regulated PD-L1 at the mRNA, protein, and membrane levels, thereby arousing the immune microenvironment of lung adenocarcinoma. Further exploration presented that CEP induced autophagy, which specifically accelerated the fusion of lysosomes with autophagosomes, ultimately leading to the degradation of PD-L1 in lung cancer cells. Mechanistically, TSPO and RILP were critical molecules through which CEP accelerated autophagic flux, as validated by drug target techniques and genetic perturbation. Finally, the findings supported the clinical translational potential of CEP plus anti-PD-L1 as a novel chemo-immunotherapy regimen. Taken together, CEP accelerates autophagy through direct inhibition of TSPO and activation of RILP, leading to PD-L1 autophagic degradation, which arouses immune microenvironment of lung adenocarcinoma. The immune regulation effects mediated by CEP prove to be a novel combination chemo-immunotherapy strategy for lung cancer treatment.