Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche
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<sup>High</sup> 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 E<sub>2</sub> (PGE<sub>2</sub>) 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.
Authors
- Evgeny Izumchenko (ORCID: https://orcid.org/0000-0003-3500-5664)
- Weijie Guo (ORCID: https://orcid.org/0000-0002-1196-5153)
- Xuejie Huang (ORCID: https://orcid.org/0000-0001-5900-678X)
- Matthias Gunzer (ORCID: https://orcid.org/0000-0002-5534-6055)
- Shuh Narumiya (ORCID: https://orcid.org/0000-0001-8062-6529)
- Daniel Leon
- Alexander T. Pearson (ORCID: https://orcid.org/0000-0003-2801-7456)
- Nishant Agrawal (ORCID: https://orcid.org/0000-0002-1361-3231)
- Yuxuan Miao (ORCID: https://orcid.org/0000-0002-1534-7993)
- Mark William Lingen (ORCID: https://orcid.org/0000-0001-9666-7608)
- Ari J. Rosenberg (ORCID: https://orcid.org/0000-0001-5908-0939)
- Everett E. Vokes (ORCID: https://orcid.org/0000-0002-8645-8068)
- Siwakorn Punyawatthananukool (ORCID: https://orcid.org/0000-0001-5148-703X)
- Benjamin Nicholson (ORCID: https://orcid.org/0000-0001-9958-7064)
- Breanna Bertacchi
- Jingyun Luan
- Andrés Hidalgo (ORCID: https://orcid.org/0000-0001-5513-555X)
- Diana Bolotin
- Iván Ballesteros (ORCID: https://orcid.org/0000-0002-6246-2353)
- Sophie Gang
Institutions
- Siriraj Hospital (TH)
- Kyoto University (JP)
- Instituto de Salud Carlos III (ES)
- Yale University (US)
- University of Chicago (US)
- May Institute (US)
- Essen University Hospital (DE)
- Universidad Carlos III de Madrid (ES)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1016/j.ccell.2025.11.001
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80