Deubiquitinase inhibitor PR‐619 potentiates colon cancer immunotherapy by inducing ferroptosis

Abstract

AbstractA substantial number of colon cancer patients do not benefit from immunotherapy using programmed cell death 1 (PD1) antibodies. Therefore, combination therapy drugs are required to improve the efficacy of colon cancer immunotherapy. Recent studies have shown that deubiquitinases are negative regulators of anti‐tumour immunity. In the present study, we investigated the effect of the deubiquitinase inhibitor PR‐619 in combination with anti‐PD1 for the treatment of colorectal cancer. The results revealed that co‐treatment with PR‐619 and anti‐PD1 significantly inhibited tumour growth in tumour‐bearing BALB/c mice compared to monotherapy with a single drug. In addition, PR‐619/anti‐PD1 combined therapy inhibited cell proliferation, promoted cell apoptosis, induced intratumor infiltration of CD8+ T cells, and enhanced the release of anti‐tumour cytokines. Moreover, PR‐619 induced ferroptosis in colon cancer cells, thereby inducing the release of damage‐associated molecular patterns that triggered anti‐tumour immunity. Finally, we discovered that PR‐619 could degrade the GPX4 protein, the high expression of which was associated with poor prognosis and blocked CD8+ T cells infiltration in colon cancer. In conclusion, PR‐619 may potentiate immunotherapy by inducing ferroptosis, and thereby promoting CD8+ T cells‐mediated anti‐tumour immunity, providing a potential strategy for colon cancer treatment.