Cancer-Associated Fibroblast-Targeted Nanomedicine in Solid Tumor Therapy: From Mechanisms of Therapeutic Resistance to Precision Stromal Modulation.

Solid tumors remain difficult to treat because their therapeutic resistance is shaped not only by malignant-cell heterogeneity but also by stromal barriers that prevent therapeutic agents and immune cells from effectively reaching and eliminating tumor cells. Among these stromal components, cancer-associated fibroblasts (CAFs) are among the most abundant and functionally influential cell populations in the tumor microenvironment. Through extracellular matrix remodeling, paracrine signaling, immune regulation, and metabolic crosstalk, CAFs profoundly influence therapeutic response and prognosis in solid tumors. As central stromal regulators, CAFs determine whether antitumor therapies can achieve effective tumor inhibition. This central regulatory role makes CAFs rational and increasingly important therapeutic targets in solid tumors. However, CAF-targeted therapy is complicated by the pronounced heterogeneity and plasticity of CAF populations. Distinct CAF subsets may exert divergent, or even opposing, effects on tumor progression and therapeutic response. Therefore, effective CAF-targeted therapy should move beyond nonspecific CAF depletion and instead focus on precise stromal modulation. Nanomedicine provides a powerful strategy to strengthen CAF-directed therapy because nanomaterials can be engineered to match the biological and spatial features of CAF-rich tumor stroma. By tuning size, charge, shape, porosity, surface ligands, biomimetic coatings, and stimulus-responsive release, nanocarriers can enhance stromal accumulation, bind CAF-associated targets, and convert CAF biology into actionable therapeutic selectivity. In this review, we summarize the biological origins, activation mechanisms, subtype heterogeneity, dual functions, and biomarker landscape of CAFs in solid tumors, and systematically discuss how CAFs drive therapeutic resistance through physical, biochemical, metabolic, and immune barriers. We then highlight current CAF-targeted nanomedicine strategies, including CAF-selective delivery, extracellular matrix remodeling, CAF reprogramming, immune microenvironment regulation, and combination with chemotherapy, radiotherapy, photothermal/photodynamic therapy, immune checkpoint blockade, and adoptive cell therapy. Finally, we discuss key translational challenges, including target specificity, deep stromal penetration, long-term safety, biomarker-guided patient stratification, scalable manufacturing, and AI-assisted nanocarrier optimization. Overall, CAF-targeted nanomedicine offers a promising route to transform the tumor stroma from a barrier to therapy into a modifiable therapeutic interface, thereby improving the precision and efficacy of solid tumor treatment.