Stress-adapted cancer-associated fibroblasts as mediators of immunosuppression and therapy resistance
4 affiliations
- 1College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
- 2Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China. Electronic address: [email protected]
- 3College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected]
- 4Sanford Stem Cell Institute, Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA, United States. Electronic address: [email protected]
Abstract
Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment (TME), shaping immune surveillance, stromal architecture, metastatic progression, and therapeutic resistance across solid tumors. Although traditionally classified into heterogeneous subtypes, emerging evidence indicates that CAF phenotypes are not fixed lineages, but dynamic stress-adaptive states continuously reshaped by hypoxia, oxidative stress, nutrient deprivation, metabolic pressure, and therapy-induced injury. These pressures reprogram CAFs transcriptional, metabolic, and secretory programs, enabling CAFs to amplify tumor-promoting signals that reinforce immunosuppression, extracellular matrix (ECM) remodeling, metastatic niche formation, and treatment resistance. Viewing CAF biology through this stress-adaptation framework provides a mechanistic explanation for the limited success of indiscriminate stromal depletion strategies and highlights the need for more selective, context-aware therapeutic intervention. In this review, we examine how microenvironmental and therapeutic stress rewires CAF identity and function across tumor progression, integrating insights from single-cell, spatial, and translational evidence. We further discuss emerging strategies aimed at disrupting stress-adaptive CAF programs, including modulation of inflammatory signaling, stromal mechanotransduction, metabolic dependencies, and senescence-associated secretory phenotypes. Reframing CAFs as dynamic stress-responsive hubs rather than static stromal subtypes may provide a conceptual foundation for next-generation stromal-targeted therapies designed to overcome immunosuppression and therapeutic resistance.
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BibTeX
@article{hu2026stressadapted,
title = {{Stress-adapted cancer-associated fibroblasts as mediators of immunosuppression and therapy resistance}},
author = {Yali Hu and Jingyao Ge and Meiqi Xin and Runqi Guo and Chengsheng Wu and Wenxue Ma},
journal = {Cancer Letters},
year = {2026},
month = jul,
doi = {10.1016/j.canlet.2026.218706},
url = {https://doi.org/10.1016/j.canlet.2026.218706},
note = {CC BY},
}
RIS
TY - JOUR
TI - Stress-adapted cancer-associated fibroblasts as mediators of immunosuppression and therapy resistance
AU - Yali Hu
AU - Jingyao Ge
AU - Meiqi Xin
AU - Runqi Guo
AU - Chengsheng Wu
AU - Wenxue Ma
PY - 2026
DA - 2026/07/03
JO - Cancer Letters
DO - 10.1016/j.canlet.2026.218706
UR - https://doi.org/10.1016/j.canlet.2026.218706
AB - Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment (TME), shaping immune surveillance, stromal architecture, metastatic progression, and therapeutic resistance across solid tumors. Although traditionally classified into heterogeneous subtypes, emerging evidence indicates that CAF phenotypes are not fixed lineages, but dynamic stress-adaptive states continuously reshaped by hypoxia, oxidative stress, nutrient deprivation, metabolic pressure, and therapy-induced injury. These pressures reprogram CAFs transcriptional, metabolic, and secretory programs, enabling CAFs to amplify tumor-promoting signals that reinforce immunosuppression, extracellular matrix (ECM) remodeling, metastatic niche formation, and treatment resistance. Viewing CAF biology through this stress-adaptation framework provides a mechanistic explanation for the limited success of indiscriminate stromal depletion strategies and highlights the need for more selective, context-aware therapeutic intervention. In this review, we examine how microenvironmental and therapeutic stress rewires CAF identity and function across tumor progression, integrating insights from single-cell, spatial, and translational evidence. We further discuss emerging strategies aimed at disrupting stress-adaptive CAF programs, including modulation of inflammatory signaling, stromal mechanotransduction, metabolic dependencies, and senescence-associated secretory phenotypes. Reframing CAFs as dynamic stress-responsive hubs rather than static stromal subtypes may provide a conceptual foundation for next-generation stromal-targeted therapies designed to overcome immunosuppression and therapeutic resistance.
SN - 0304-3835
SN - 1872-7980
ER -