Pirenzepine exhibits anti-prostate cancer activity and enhances checkpoint inhibitor-based immunotherapy by targeting...

Therapeutic options targeting programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for use in human malignancies, showing clinical benefits. Nonetheless, a significant number of patients, particularly those with prostate cancer (PCa), show poor response to anti-PD-1/PD-L1 therapies, highlighting the necessity to explore supportive strategies that could enhance conventional PD-1/PD-L1-targeting immunotherapy.

PCa cell lines DU145 and RM1 were used to investigate the effects of pirenzepine (PZP) on the proliferation, colony formation, and migration of PCa cells in vitro. A subcutaneous tumor model bearing DU145 and RM1 was established to evaluate the anti-tumor effect in vivo. Lentivirus transfection and quantitative polymerase chain reaction (qPCR) assays were conducted to investigate the role of STING (endoplasmic reticulum-associated protein stimulator of interferon genes) in the antitumor mechanisms of PZP. The infiltration of CD8⁺ T cells in tumor tissues was examined using immunohistochemistry. The RM1 subcutaneous tumor model was employed to assess the combined effects of PZP and anti-programmed cell death 1 antibody (anti-PD1) immune checkpoint blockade therapy.

The in vitro and in vivo experiment results indicated that PZP suppressed the proliferation, colony formation, and migration of PCa cells in a dose-dependent manner. Notably, PZP also promoted CD8⁺ T cell infiltration and enhanced the anti-PD1 therapeutic effect on PCa. Mechanistically, the results preliminarily indicated that PZP impeded PCa progression and stimulated tumor immune response by upregulating STING expression.

Our results revealed that PZP impaired the malignant biological behavior of PCa and enhanced antitumor immunity. These findings may provide a theoretical basis for combining PZP with anti-PD1 immune checkpoint blockade therapy on PCa.