Although iron is required for cell proliferation, iron‐dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron‐mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron‐responsive element‐binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)‐mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage‐associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor‐reactive T‐cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1‐IREB2‐TFRC signaling axis in host antitumor immunity.

中文翻译：

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去泛素化酶 OTUD1 增强铁转运并增强宿主抗肿瘤免疫

尽管细胞增殖需要铁，但铁依赖性程序性细胞死亡是肿瘤生长和转移的关键屏障。新出现的证据表明，铁介导的脂质氧化也有助于免疫根除癌症。然而，癌症中铁代谢的调节机制仍不清楚。在这里，我们将 OTUD1 鉴定为铁反应元件结合蛋白 2 (IREB2) 的去泛素化酶，在结直肠癌中选择性降低。临床上，OTUD1的下调与癌症的不良结果高度相关。从机制上讲，OTUD1 通过去泛素化和稳定 IREB2 促进转铁蛋白受体蛋白 1 (TFRC) 介导的铁转运，导致 ROS 生成增加和铁死亡。而且，OTUD1 的存在促进了损伤相关分子模式 (DAMP) 的释放，进而募集白细胞并增强宿主免疫反应。相反，OTUD1的消耗限制了肿瘤反应性T细胞的积累并加剧了结肠癌的进展。我们的数据表明 OTUD1 在铁转运中起刺激作用，并突出了 OTUD1-IREB2-TFRC 信号轴在宿主抗肿瘤免疫中的重要性。