Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment (TME) need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MBOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL-1beta+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MBOAT1 expression via IL-1beta/IL-1R1/NF-kappaB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL-8 and S100A9 to replenish the neutrophil pool in the TME. Ferroptotic neutrophils in turn fostered Fer-CD4 T cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL-1beta+ CD4+ T cells or IL-1R1+ neutrophils broke the crosstalk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer.

中文翻译：

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铁死亡中性粒细胞诱导乳腺癌免疫抑制和化疗耐药


在肿瘤细胞中诱导铁死亡正在成为治疗传统治疗方式难治性恶性肿瘤的一种策略。然而，需要更好地了解肿瘤微环境 （TME） 中免疫细胞铁死亡的后果，以实现这种方法的潜力。在这项研究中，我们发现化疗耐药乳腺癌中的中性粒细胞对铁死亡高度敏感。化疗耐药相关嗜中性粒细胞中酰基转移酶 MBOAT1 的减少诱导了磷脂重编程，将偏好从单不饱和脂肪酸转变为多不饱和脂肪酸，这增加了它们对铁死亡的易感性。铁死亡中性粒细胞分泌 PGE2 、 IDO 和氧化脂质，抑制抗肿瘤 CD8+ T 细胞的增殖和细胞毒性。此外，中性粒细胞铁死亡与 IL-1β + CXCL3 + CD4 + （Fer-CD4） T 淋巴细胞的一个独特亚群密切相关，这些细胞在化疗耐药肿瘤中富集。Fer-CD4 T 细胞通过 IL-1β/IL-1R1/NF-kappaB 信号传导调节 MBOAT1 表达，从而协调中性粒细胞铁死亡。此外，Fer-CD4 T 细胞分泌 CXCL3 、 IL-8 和 S100A9 以补充 TME 中的中性粒细胞库。铁死亡中性粒细胞反过来促进 Fer-CD4 T 细胞分化。在自发性肿瘤发生小鼠模型中，靶向 IL-1β+ CD4+ T 细胞或 IL-1R1+ 中性粒细胞打破了串扰，抑制了中性粒细胞铁死亡，增强了抗肿瘤免疫力，克服了化疗耐药性。总体而言，这些发现揭示了中性粒细胞铁死亡在塑造免疫景观中的作用，并为恢复乳腺癌的免疫监视和化疗敏感性提出了有吸引力的靶点。