Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche

Weijie Guo; Jingyun Luan; Xuejie Huang; Daniel Leon; Sophie Gang; Benjamin Nicholson; Breanna Bertacchi; Diana Bolotin; Mark W. Lingen; Alexander T. Pearson; Evgeny Izumchenko; Ari J. Rosenberg; Nishant Agrawal; Everett E. Vokes; Siwakorn Punyawatthananukool; Shuh Narumiya; Matthias Gunzer; Iván Ballesteros; Andrés Hidalgo; Yuxuan Miao

doi:10.1016/j.ccell.2025.11.001

Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche

Weijie Guo
, Jingyun Luan
, Xuejie Huang
, Daniel Leon
, Sophie Gang
, Benjamin Nicholson
, Breanna Bertacchi
, Diana Bolotin
, Mark W. Lingen
, Alexander T. Pearson
, Evgeny Izumchenko
, Ari J. Rosenberg
, Nishant Agrawal
, Everett E. Vokes
, Siwakorn Punyawatthananukool
, Shuh Narumiya
, Matthias Gunzer
, Iván Ballesteros
, Andrés Hidalgo
, Yuxuan Miao

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

5 Scopus citations

Abstract

The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2^High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E₂ (PGE₂) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.

Original language	English
Pages (from-to)	94-111.e11
Journal	Cancer Cell
Volume	44
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2025.11.001
State	Published - 12 Jan 2026
Externally published	Yes

Keywords

Fads1
Sox2
arachidonic acid
cancer relapse
immunotherapy
interferon response
prostaglandin E2
squamous cell carcinoma
tumor-associated neutrophils
tumor-initiaiting stem cells

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10.1016/j.ccell.2025.11.001

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Guo, W., Luan, J., Huang, X., Leon, D., Gang, S., Nicholson, B., Bertacchi, B., Bolotin, D., Lingen, M. W., Pearson, A. T., Izumchenko, E., Rosenberg, A. J., Agrawal, N., Vokes, E. E., Punyawatthananukool, S., Narumiya, S., Gunzer, M., Ballesteros, I., Hidalgo, A., & Miao, Y. (2026). Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche. Cancer Cell, 44(1), 94-111.e11. https://doi.org/10.1016/j.ccell.2025.11.001

@article{b439162619364171a5453af8b6ff554f,

title = "Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche",

abstract = "The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E2 (PGE2) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.",

keywords = "Fads1, Sox2, arachidonic acid, cancer relapse, immunotherapy, interferon response, prostaglandin E2, squamous cell carcinoma, tumor-associated neutrophils, tumor-initiaiting stem cells",

author = "Weijie Guo and Jingyun Luan and Xuejie Huang and Daniel Leon and Sophie Gang and Benjamin Nicholson and Breanna Bertacchi and Diana Bolotin and Lingen, \{Mark W.\} and Pearson, \{Alexander T.\} and Evgeny Izumchenko and Rosenberg, \{Ari J.\} and Nishant Agrawal and Vokes, \{Everett E.\} and Siwakorn Punyawatthananukool and Shuh Narumiya and Matthias Gunzer and Iv{\'a}n Ballesteros and Andr{\'e}s Hidalgo and Yuxuan Miao",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2026",

month = jan,

day = "12",

doi = "10.1016/j.ccell.2025.11.001",

language = "English",

volume = "44",

pages = "94--111.e11",

journal = "Cancer Cell",

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Guo, W, Luan, J, Huang, X, Leon, D, Gang, S, Nicholson, B, Bertacchi, B, Bolotin, D, Lingen, MW, Pearson, AT, Izumchenko, E, Rosenberg, AJ, Agrawal, N, Vokes, EE, Punyawatthananukool, S, Narumiya, S, Gunzer, M, Ballesteros, I, Hidalgo, A & Miao, Y 2026, 'Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche', Cancer Cell, vol. 44, no. 1, pp. 94-111.e11. https://doi.org/10.1016/j.ccell.2025.11.001

TY - JOUR

T1 - Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche

AU - Guo, Weijie

AU - Luan, Jingyun

AU - Huang, Xuejie

AU - Leon, Daniel

AU - Gang, Sophie

AU - Nicholson, Benjamin

AU - Bertacchi, Breanna

AU - Bolotin, Diana

AU - Lingen, Mark W.

AU - Pearson, Alexander T.

AU - Izumchenko, Evgeny

AU - Rosenberg, Ari J.

AU - Agrawal, Nishant

AU - Vokes, Everett E.

AU - Punyawatthananukool, Siwakorn

AU - Narumiya, Shuh

AU - Gunzer, Matthias

AU - Ballesteros, Iván

AU - Hidalgo, Andrés

AU - Miao, Yuxuan

PY - 2026/1/12

Y1 - 2026/1/12

N2 - The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E2 (PGE2) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.

AB - The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E2 (PGE2) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.

KW - Fads1

KW - Sox2

KW - arachidonic acid

KW - cancer relapse

KW - immunotherapy

KW - interferon response

KW - prostaglandin E2

KW - squamous cell carcinoma

KW - tumor-associated neutrophils

KW - tumor-initiaiting stem cells

UR - https://www.scopus.com/pages/publications/105024313912

U2 - 10.1016/j.ccell.2025.11.001

DO - 10.1016/j.ccell.2025.11.001

M3 - Article

C2 - 41349542

AN - SCOPUS:105024313912

SN - 1535-6108

VL - 44

SP - 94-111.e11

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche

Abstract

Keywords

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