Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-03-28 DOI:10.1016/j.immuni.2025.03.002

Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L. Chan, Bo Wei, Philip L. Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C. Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, Xiang H.-F. Zhang

{"title":"Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer","authors":"Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L. Chan, Bo Wei, Philip L. Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C. Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, Xiang H.-F. Zhang","doi":"10.1016/j.immuni.2025.03.002","DOIUrl":null,"url":null,"abstract":"The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":25.5000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2025.03.002","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.

Abstract Image

查看原文本刊更多论文

肿瘤来源的花生四烯酸重编程中性粒细胞，促进三阴性乳腺癌的免疫抑制和治疗抵抗

免疫检查点阻断联合化疗是三阴性乳腺癌（TNBC）的标准治疗方案。然而，最初，反应性肿瘤仍然可以复发，这表明获得性耐药机制仍然知之甚少。在此，我们发现TNBC细胞在抗程序性细胞死亡蛋白-1 （anti-PD-1）和化疗治疗后积累中性脂质。破坏癌细胞中脂滴的形成可逆转耐药性并减轻免疫抑制微环境。单细胞RNA测序显示中性粒细胞亚群表现出与邻近肿瘤细胞相似的脂质负载表型。机制上，肿瘤来源的细胞外囊泡携带脂质，包括花生四烯酸（AA），介导中性粒细胞重编程。阻断饮食摄入omega-6脂肪酸或抑制脂肪酸延伸以合成AA可恢复抗肿瘤免疫，并使耐药肿瘤对抗pd -1和化疗重新敏感。在人类患者中，AA代谢相关途径与中性粒细胞富集相关。总之，我们证明了TNBC细胞中的脂质积累如何导致免疫抑制和治疗抵抗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.