Cytokine context shapes antigen-presenting and matrix-producing states of cancer-associated fibroblasts.
7 affiliations
- 1Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
- 2Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
- 3Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
- 4Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- 5Endoscopy Center and Endoscopy Research Institute, Shanghai Collaborative Innovation Center of Endoscopy, Zhongshan Hospital, Fudan University, Shanghai, China.
- 6Department of Ultrasound, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- 7Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Key Laboratory of Gut Microecology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China. [email protected].
Abstract
Cancer-associated fibroblasts (CAFs) exhibit remarkable functional heterogeneity, with conserved subtypes observed across diverse malignancies. However, their shared roles in shaping the tumor microenvironment (TME) and their dynamic plasticity remain incompletely understood. In this study, through integrated single-cell and spatial transcriptomic profiling across four cancer types, we identified two distinct immunomodulatory CAF states, termed antigen-presenting CAFs (apCAFs) and matrix-producing CAFs (mCAFs). Across multiple solid tumors, apCAFs were associated with enhanced anti-tumor immune features and favorable prognosis, whereas mCAFs were associated with immunosuppressive characteristics and poorer clinical outcomes. Spatial analyses revealed distinct localization patterns of apCAFs and mCAFs within the TME. Functionally, patient-derived apCAFs promoted T-cell migration, proliferation, and activation, whereas mCAFs suppressed these responses in vitro. Pan-cancer analyses further revealed a strong inverse correlation between apCAF and mCAF abundance across tumor tissues. Mechanistically, IFN-γ and TGF-β-associated signaling contexts were linked to distinct CAF transcriptional programs, with IFN-γ promoting apCAF-associated features and TGF-β favoring mCAF-associated features, suggesting a potential role of cytokine context in shaping CAF state heterogeneity. Clinically, apCAFs correlated with favorable immunotherapy response, whereas mCAFs predicted poor therapeutic outcomes. Collectively, these findings identify conserved immunomodulatory CAF subtypes across cancers, reveal distinct cytokine-associated CAF programs, and support stromal reprogramming as a promising strategy to enhance immunotherapy efficacy.
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BibTeX
@article{song2026cytokine,
title = {{Cytokine context shapes antigen-presenting and matrix-producing states of cancer-associated fibroblasts.}},
author = {Feifei Song and Qi Chen and Dengfeng Huang and Youhua Zhang and Dongyan Han and Wei Rao and Man Li and Yaohui Gao and Renfeng Zhang and Huiyuan Zhu and Shufei Wang and Xiao Jiang and Shengli Lin and Dexi Bi and Haixian Zhang and Qing Wei and Huanlong Qin},
journal = {Signal transduction and targeted therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02965-1},
url = {https://europepmc.org/article/MED/42897126},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cytokine context shapes antigen-presenting and matrix-producing states of cancer-associated fibroblasts.
AU - Feifei Song
AU - Qi Chen
AU - Dengfeng Huang
AU - Youhua Zhang
AU - Dongyan Han
AU - Wei Rao
AU - Man Li
AU - Yaohui Gao
AU - Renfeng Zhang
AU - Huiyuan Zhu
AU - Shufei Wang
AU - Xiao Jiang
AU - Shengli Lin
AU - Dexi Bi
AU - Haixian Zhang
AU - Qing Wei
AU - Huanlong Qin
PY - 2026
DA - 2026/10/20
JO - Signal transduction and targeted therapy
DO - 10.1038/s41392-026-02965-1
UR - https://europepmc.org/article/MED/42897126
AB - Cancer-associated fibroblasts (CAFs) exhibit remarkable functional heterogeneity, with conserved subtypes observed across diverse malignancies. However, their shared roles in shaping the tumor microenvironment (TME) and their dynamic plasticity remain incompletely understood. In this study, through integrated single-cell and spatial transcriptomic profiling across four cancer types, we identified two distinct immunomodulatory CAF states, termed antigen-presenting CAFs (apCAFs) and matrix-producing CAFs (mCAFs). Across multiple solid tumors, apCAFs were associated with enhanced anti-tumor immune features and favorable prognosis, whereas mCAFs were associated with immunosuppressive characteristics and poorer clinical outcomes. Spatial analyses revealed distinct localization patterns of apCAFs and mCAFs within the TME. Functionally, patient-derived apCAFs promoted T-cell migration, proliferation, and activation, whereas mCAFs suppressed these responses in vitro. Pan-cancer analyses further revealed a strong inverse correlation between apCAF and mCAF abundance across tumor tissues. Mechanistically, IFN-γ and TGF-β-associated signaling contexts were linked to distinct CAF transcriptional programs, with IFN-γ promoting apCAF-associated features and TGF-β favoring mCAF-associated features, suggesting a potential role of cytokine context in shaping CAF state heterogeneity. Clinically, apCAFs correlated with favorable immunotherapy response, whereas mCAFs predicted poor therapeutic outcomes. Collectively, these findings identify conserved immunomodulatory CAF subtypes across cancers, reveal distinct cytokine-associated CAF programs, and support stromal reprogramming as a promising strategy to enhance immunotherapy efficacy.
SN - 2095-9907
SN - 2059-3635
ER -