Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA.
Cell Metab. 2023 Oct 3;35(10):1688-1703.e10. doi: 10.1016/j.cmet.2023.09.004.
Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.
转移导致乳腺癌相关死亡。肿瘤浸润中性粒细胞（TINs）造成免疫抑制并促进转移。TIN 治疗性耗竭可能增强免疫疗法，但识别在 TINs 中高度表达且功能必需但在肿瘤外中性粒细胞中低表达的治疗靶点仍然是一个挑战。在这里，我们使用单细胞 RNA 测序比较了小鼠乳腺肿瘤模型中的 TINs 和循环中性粒细胞，发现延胡索酸酶 1（Acod1）是小鼠 TINs 中上调最明显的代谢酶，并验证了人类 TINs 中 Acod1 的高表达。Acod1 通过 GM-CSF-JAK/STAT5-C/EBPβ 通路激活，产生 ITCA，介导 Nrf2 依赖的对铁死亡的防御，并维持 TINs 的持久性。Acod1 缺失可减少 TIN 浸润，限制转移（但不限制原发性肿瘤），增强抗肿瘤 T 细胞免疫，并提高免疫检查点阻断的疗效。我们的研究结果揭示了 TINs 如何通过 Acod1 依赖性免疫代谢开关逃避铁死亡，并确立 Acod1 作为抵消免疫抑制和改善转移性免疫治疗的靶点。
