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

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; David G. Edwards; Livia S. Eberlin; Xiang H.F. Zhang

doi:10.1016/j.immuni.2025.03.002

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

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 LiuDavid G. Edwards, Livia S. Eberlin, Xiang H.F. Zhang

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	909-925.e7
Journal	Immunity
Volume	58
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2025.03.002
State	Published - 8 Apr 2025
Externally published	Yes

Keywords

arachidonic acid
extracellular vesicles
immunotherapy
neutrophils
triple negative breast cancer

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10.1016/j.immuni.2025.03.002

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Yu, L., Liebenberg, K., Shen, Y., Liu, F., Xu, Z., Hao, X., Wu, L., Zhang, W., Chan, H. L., Wei, B., Lorenzi, P. L., Gao, Y., Bado, I., Becerra-Dominguez, L., Rivas, C. H., Aguirre, S., Pingel, B. C., Wu, Y. H., Ding, Y., ... Zhang, X. H. F. (2025). Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer. Immunity, 58(4), 909-925.e7. https://doi.org/10.1016/j.immuni.2025.03.002

@article{58c807dd5caa48fcbac3f631f7d6a896,

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

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.",

keywords = "arachidonic acid, extracellular vesicles, immunotherapy, neutrophils, triple negative breast cancer",

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

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = apr,

day = "8",

doi = "10.1016/j.immuni.2025.03.002",

language = "English",

volume = "58",

pages = "909--925.e7",

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Yu, L, Liebenberg, K, Shen, Y, Liu, F, Xu, Z, Hao, X, Wu, L, Zhang, W, Chan, HL, Wei, B, Lorenzi, PL, Gao, Y, Bado, I, Becerra-Dominguez, L, Rivas, CH, Aguirre, S, Pingel, BC, Wu, YH, Ding, Y, Liu, J, Edwards, DG, Eberlin, LS & Zhang, XHF 2025, 'Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer', Immunity, vol. 58, no. 4, pp. 909-925.e7. https://doi.org/10.1016/j.immuni.2025.03.002

TY - JOUR

T1 - Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer

AU - Yu, Liqun

AU - Liebenberg, Keziah

AU - Shen, Yichao

AU - Liu, Fengshuo

AU - Xu, Zhan

AU - Hao, Xiaoxin

AU - Wu, Ling

AU - Zhang, Weijie

AU - Chan, Hilda L.

AU - Wei, Bo

AU - Lorenzi, Philip L.

AU - Gao, Yang

AU - Bado, Igor

AU - Becerra-Dominguez, Luis

AU - Rivas, Charlotte Helena

AU - Aguirre, Sergio

AU - Pingel, Bradley C.

AU - Wu, Yi Hsuan

AU - Ding, Yunfeng

AU - Liu, Jun

AU - Edwards, David G.

AU - Eberlin, Livia S.

AU - Zhang, Xiang H.F.

PY - 2025/4/8

Y1 - 2025/4/8

N2 - 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.

AB - 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.

KW - arachidonic acid

KW - extracellular vesicles

KW - immunotherapy

KW - neutrophils

KW - triple negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=105001652916&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2025.03.002

DO - 10.1016/j.immuni.2025.03.002

M3 - Article

AN - SCOPUS:105001652916

SN - 1074-7613

VL - 58

SP - 909-925.e7

JO - Immunity

JF - Immunity

IS - 4

ER -

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

Abstract

Keywords

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