Stress-adapted cancer-associated fibroblasts as mediators of immunosuppression and therapy resistance

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.