Cancer-associated fibroblast–tumor organoid models of therapy resistance: mechanisms, materials, and translational potential

Therapy resistance in solid tumors is shaped not only by cancer-cell evolution but also by cancer-associated fibroblasts (CAFs), which regulate signaling, extracellular-matrix organization, metabolism, and immune-cell access. Patient-derived tumor organoids reconstituted with CAFs offer a tractable human system for resolving these stromal effects while preserving epithelial heterogeneity and three-dimensional architecture. This narrative review examines how CAF heterogeneity, plasticity, tissue origin, passage history, and autologous pairing influence model behavior; compares matrix-embedded, spatially organized, microfluidic, perfused, and bioprinted platforms; and evaluates the materials parameters that govern mechanotransduction, transport, and drug response. We distinguish mechanisms directly demonstrated in CAF–organoid co-cultures from those inferred from two-dimensional, animal, or non-organoid studies, with particular attention to paracrine and contact-dependent signaling, extracellular-matrix mechanics, metabolic coupling, and immune regulation. Current evidence shows that CAF inclusion can reveal patient-dependent resistance and reciprocal tumor–stroma state changes that are not apparent in epithelial monoculture. However, culture medium, matrix composition, cell ratio, spatial organization, and CAF-state drift remain major sources of bias. CAF–organoid models may support mechanism-guided combination testing and functional precision oncology, but their added predictive value requires standardized reporting, multicenter benchmarking, and prospective clinical validation.