Cancer-associated fibroblasts at the crossroads of tumor progression and therapy resistance: from heterogeneity to precision reprogramming

Cancer-associated fibroblasts (CAFs) are pivotal regulators of the tumor microenvironment (TME), driving malignancy through extracellular matrix remodeling, paracrine and metabolic crosstalk, angiogenesis, fibrosis, and immune suppression. Emerging single-cell and spatial multi-omics have revealed CAF heterogeneity and plasticity, with subtypes such as myofibroblastic, inflammatory, antigen-presenting, and metabolic CAFs exerting context-dependent functions that can either promote or restrain tumor growth. This duality cautions against indiscriminate stromal ablation and highlights the need for precision strategies. CAFs also mediate resistance to chemotherapy, radiotherapy, targeted agents, and immunotherapy by creating physical and biochemical barriers and fostering immune exclusion. Therapeutic approaches span depletion strategies, pathway inhibitors, and stromal reprogramming using vitamin D receptor agonists, retinoids, and epigenetic modulators, often in combination with immunotherapies. However, CAF plasticity and the lack of exclusive markers remain major challenges. This review positions CAFs as dynamic regulators of cancer hallmarks and argues for a paradigm shift toward precision stromal oncology, where the trajectory from CAF depletion to CAF reprogramming and CAF-guided combinatorial therapies reshapes cancer treatment itself.