Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies. Ferroptosis, a form of cell death that is characterized by iron accumulation and lipid peroxidation, has not yet been fully evaluated from this perspective. Here we present an inducible model of ferroptosis, distinguishing three phases in the process—‘initial’ associated with lipid peroxidation, ‘intermediate’ correlated with ATP release and ‘terminal’ recognized by HMGB1 release and loss of plasma membrane integrity—that serves as tool to study immune cell responses to ferroptotic cancer cells. Co-culturing ferroptotic cancer cells with dendritic cells (DC), reveals that ‘initial’ ferroptotic cells decrease maturation of DC, are poorly engulfed, and dampen antigen cross-presentation. DC loaded with ferroptotic, in contrast to necroptotic, cancer cells fail to protect against tumor growth. Adding ferroptotic cancer cells to immunogenic apoptotic cells dramatically reduces their prophylactic vaccination potential. Our study thus shows that ferroptosis negatively impacts antigen presenting cells and hence the adaptive immune response, which might hinder therapeutic applications of ferroptosis induction.

免疫原性细胞死亡显着有助于抗癌疗法的成功，但不同细胞死亡方式的免疫原性差异很大。铁死亡是一种以铁积累和脂质过氧化为特征的细胞死亡形式，尚未从这个角度进行全面评估。在这里，我们提出了一个可诱导的铁下垂模型，区分了该过程中的三个阶段——与脂质过氧化相关的“初始”阶段、与 ATP 释放相关的“中间”阶段和由 HMGB1 释放和质膜完整性丧失识别的“终端”阶段——作为工具研究免疫细胞对铁死亡癌细胞的反应。将铁死亡癌细胞与树突状细胞 (DC) 共培养，揭示了“初始”铁死亡细胞会降低 DC 的成熟度，被吞噬能力差，并抑制抗原交叉呈递。与坏死性凋亡相比，载有铁死亡的 DC 无法防止肿瘤生长。将铁死亡癌细胞添加到免疫原性凋亡细胞中会显着降低其预防性疫苗接种的潜力。因此，我们的研究表明，铁死亡对抗原呈递细胞产生负面影响，从而影响适应性免疫反应，这可能会阻碍铁死亡诱导的治疗应用。