DeCAF defines clinical fibroblast subtypes and multidimensional tumor-stroma crosstalk shaping prognosis and immunotherapy response

Xianlu Laura Peng; Ian C McCabe; Elena V Kharitonova; Yi Xu; Ryan T Zhao; Changfei Luan; Joseph F Kearney; Nancy P Kren; Arthi Hariharan; Jaewon J Lee; Justin Su; Priscilla S Chan; Ashley B Morrison; Michelle E LaBella; Silvia G Herera Loeza; Ashley Cliff; Hong Jin Kim; Yuliya Pylayeva-Gupta; Susan Tsai; Brian A Belt; Roheena Z Panni; David C Linehan; Shawn M Gomez; Jeffrey S Damrauer; Alina C Iuga; William Y Kim; Naim U Rashid; Jen Jen Yeh

doi:10.1016/j.xcrm.2026.102611

DeCAF defines clinical fibroblast subtypes and multidimensional tumor-stroma crosstalk shaping prognosis and immunotherapy response

Cell Rep Med. 2026 Feb 17;7(2):102611. doi: 10.1016/j.xcrm.2026.102611.

Authors

Xianlu Laura Peng¹, Ian C McCabe², Elena V Kharitonova³, Yi Xu⁴, Ryan T Zhao⁵, Changfei Luan⁵, Joseph F Kearney⁶, Nancy P Kren⁵, Arthi Hariharan⁵, Jaewon J Lee⁶, Justin Su⁵, Priscilla S Chan⁵, Ashley B Morrison⁵, Michelle E LaBella⁶, Silvia G Herera Loeza⁵, Ashley Cliff⁵, Hong Jin Kim⁷, Yuliya Pylayeva-Gupta⁸, Susan Tsai⁹, Brian A Belt¹⁰, Roheena Z Panni¹¹, David C Linehan¹⁰, Shawn M Gomez¹², Jeffrey S Damrauer¹³, Alina C Iuga¹⁴, William Y Kim¹⁵, Naim U Rashid¹⁶, Jen Jen Yeh¹⁷

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: laura.peng@med.unc.edu.
² Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Department of Surgery, Ohio State University Medical Center, Columbus, OH 43210, USA.
¹⁰ Department of Surgery, University of Rochester, Rochester, NY 14642, USA.
¹¹ Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
¹² Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lampe Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: wykim@med.unc.edu.
¹⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: nur2@email.unc.edu.
¹⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jjyeh@med.unc.edu.

Abstract

Single-cell RNA sequencing (scRNA-seq) studies have uncovered distinct cancer-associated fibroblast (CAF) populations. While useful as a biological framework, no studies have conclusively defined CAF subtypes with clinical significance. We define restraining (rest) and promoting (pro) CAFs in patient samples that are both prognostic and predictive of therapy response in multiple tumor types. We uncover distinct clinical and spatial interactions between pro- and restCAF subtypes and basal-like and classical tumor subtypes that support tumor-stroma crosstalk. Finally, we find striking differences in the immune contexture of pro- and restCAF tumors where restCAF-dominant tumors are more responsive to immune checkpoint inhibition and proCAF-dominant tumors are more responsive to myeloid inhibition in clinical trials. This work defines CAF subtypes that are clinically robust, prognostic, and predictive of immunotherapy response and provides a single-sample classifier, determination of pro- and restCAF subtypes (DeCAF), which is clinically actionable.

Keywords: CAF; CAF subtype; PDAC; TME; cancer-associated fibroblast; classifier; pancreatic cancer; spatial transcriptomics; tumor microenvironment; tumor-stroma interaction.

MeSH terms

Cancer-Associated Fibroblasts* / immunology
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Fibroblasts
Humans
Immunotherapy* / methods
Neoplasms* / genetics
Neoplasms* / immunology
Neoplasms* / pathology
Neoplasms* / therapy
Prognosis
Single-Cell Analysis
Tumor Microenvironment

Grants and funding

T32 CA244125/CA/NCI NIH HHS/United States