去泛素化酶抑制剂 PR-619 通过诱导铁死亡增强结肠癌免疫治疗

A 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.