结直肠癌患者中有相当数量的患者对使用程序性细胞死亡1 (PD1) 抗体的免疫治疗没有受益。因此，需要联合治疗药物以改善结直肠癌免疫治疗的疗效。最近的研究显示去泛素化酶是抗肿瘤免疫的负向调节因子。在本研究中，我们调查了去泛素化酶抑制剂PR-619与抗-PD1联合治疗结肠癌的效果。结果表明，与单药治疗相比，PR-619和抗-PD1的联合治疗显著抑制了荷瘤BALB/c小鼠的肿瘤生长。此外，PR-619/抗-PD1联合治疗抑制了细胞增殖，促进了细胞凋亡，诱导了CD8+ T细胞内瘤内浸润，并增强了抗肿瘤细胞因子的释放。此外，PR-619还诱导了结肠癌细胞的铁死亡，从而诱发了损伤相关分子模式的释放，并引发了抗肿瘤免疫反应。最后，我们发现PR-619可以降解与恶性预后相关的GPX4蛋白，并阻止CD8+ T细胞浸润结肠癌。总之，通过诱导铁死亡，PR-619可能增强免疫治疗，从而促进CD8+ T细胞介导的抗肿瘤免疫，为结直肠癌治疗提供了潜在策略。© 2023 John Wiley & Sons Ltd.

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.© 2023 John Wiley & Sons Ltd.