Targeting Cancer-Associated Fibroblasts with Small-Molecule Inhibitors: Molecular Mechanisms and Therapeutic Potential.

The multifaceted role of cancer-associated fibroblasts (CAFs) in orchestrating extracellular matrix remodeling, immune evasion, and therapeutic resistance positions these stromal cells as critical yet underexploited nodes in the tumor microenvironment (TME). While small-molecule agents offer practical advantages over biologics for stromal modulation, a systematic understanding of their mechanistic diversity and translational barriers remains incomplete. To address this gap, this review consolidates current knowledge on the principal signaling axes-TGF-β/STAT3, NF-κB, Notch, Hedgehog, PI3K/AKT, and CXCL12/CXCR4-that sustain CAF activation and pathogenic functions. Distinct from prior CAF reviews, particular emphasis is placed on the structure-activity refinement (SAR) of fibroblast activation protein (FAP)-targeted small-molecule ligands and on pharmacokinetic optimization via fatty acid conjugation and porphyrin integration that substantially improve tumor retention. Representative pharmacological inhibitors-including nicotinamide N-methyltransferase (NNMT), phosphodiesterase 5A (PDE5A), and NADPH oxidase 4 (NOX4) inhibitors-are evaluated for their capacities to remodel immunosuppressive networks, with attention to their synergism when combined with chemotherapeutic agents, immune checkpoint blockers, or antibody-drug conjugates. Emerging evidence indicates that CAF heterogeneity and plasticity pose fundamental obstacles to monotherapy efficacy, whereas rationally designed combination regimens produce superior antitumor outcomes in preclinical models. We further identify key knowledge gaps-including the lack of CAF-subset-selective drugs, unresolved pharmacotoxicology of pan-FAP inhibition, and limited biomarker-guided patient stratification-and discuss translational and regulatory barriers that must be overcome before widespread clinical adoption. Collectively, this review argues that the future of CAF-directed pharmacotherapy lies not in indiscriminate depletion but in subset-selective reprogramming, and that clinical success will increasingly depend on biomarker-guided patient stratification and mechanistically anchored multidrug scheduling rather than on isolated target inhibition.