Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.

尽管铁死亡在杀死肿瘤细胞中的作用已得到充分证实，但最近的研究表明铁死亡诱导剂还通过杀死中性粒细胞来破坏抗肿瘤免疫，从而意外地刺激肿瘤生长，提出了铁死亡是否能有效抑制体内肿瘤发展的严重问题。通过全基因组 CRISPR-Cas9 筛选，我们发现了 pleckstrin同源样结构域家族 A 成员 2 (PHLDA2) 介导的铁死亡途径，该途径既不依赖于 ACSL4，也不需要常见的铁死亡诱导剂。 PHLDA2 介导的铁死亡通过磷脂酸 (PA) 对高水平活性氧(ROS)的过氧化作用。在缺乏常见的铁死亡诱导剂的情况下，ROS 诱导的铁死亡对于肿瘤生长至关重要；引人注目的是，PHLDA2 的缺失消除了 ROS 诱导的铁死亡并促进肿瘤生长，但在免疫缺陷和免疫功能正常的小鼠肿瘤模型中对正常组织没有明显影响。这些数据表明，PHLDA2 介导的 PA 过氧化触发了对肿瘤抑制至关重要的独特的铁死亡反应，并揭示了 PHLDA2 介导的铁死亡在体内自然发生，无需铁死亡诱导剂的任何治疗。