脂质过氧化依赖性铁死亡已成为肿瘤治疗的新兴策略。然而，目前的策略不仅选择性诱导恶性细胞中的铁死亡，而且同时触发免疫细胞中的铁死亡，这会损害抗肿瘤免疫。在这里，我们使用细胞内蛋白质印迹分析结合无偏倚的药物筛选来鉴定化合物 N6F11 作为铁死亡诱导剂，它触发谷胱甘肽过氧化物酶 4 (GPX4) 的降解，谷胱甘肽过氧化物酶 4 (GPX4) 是一种关键的铁死亡抑制剂，特别是在癌细胞中。 N6F11不会引起免疫细胞中GPX4的降解，包括树突状细胞、T细胞、自然杀伤细胞和中性粒细胞。从机制上讲，N6F11 与癌细胞中包含 25 (TRIM25) 的 E3 泛素连接酶三联基序的 RING 结构域结合，触发 TRIM25 介导的 GPX4 K48 连接泛素化，导致其蛋白酶体降解。从功能上讲，N6F11 治疗引起铁死亡癌细胞死亡，从而启动由 CD8 T 细胞介导的 HMGB1 依赖性抗肿瘤免疫。 N6F11 还使晚期癌症模型中针对 CD274/PD-L1 的免疫检查点封锁变得敏感，包括由 KRAS 和 TP53 突变驱动的基因工程小鼠胰腺癌模型。这些发现可能会建立一种安全有效的策略来增强铁死亡驱动的抗肿瘤免疫。

Lipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.