Cancer-associated and non-neoplastic fibrosis: Comparative mechanisms and emerging antifibrotic strategies

Fibrosis is a maladaptive tissue-remodeling process characterized by persistent fibroblast activation, excessive extracellular matrix deposition, and progressive tissue stiffening. Beyond non-neoplastic disorders, fibrosis is also a hallmark of several solid tumors, where it promotes immune evasion, impaired drug delivery, and therapeutic resistance, particularly in pancreatic, hepatocellular, colorectal, and triple-negative breast cancers. In this review, we comparatively analyze fibrosis across non-neoplastic and neoplastic conditions, using idiopathic pulmonary fibrosis as a reference model and comparing it with highly fibrotic tumors. We focus on conserved biological pathways, including TGF-β signaling, ECM remodeling, mechanotransduction, and fibroblast-tomyofibroblast activation, as well as on stromal heterogeneity and the role of cancer-associated fibroblast subsets in tumor progression and immune modulation. We also critically discuss current antifibrotic therapeutic strategies targeting ECM components, fibroblast activation, stromal signaling, and tumor–stroma interactions, highlighting both preclinical rationale and translational limitations. Finally, we examine emerging approaches such as mesenchymal stromal cell-based platforms and drug repurposing strategies bridging oncology and fibrotic diseases. Overall, this review underscores how comparative analysis of cancerous and non-cancerous fibrosis may help identify shared therapeutic vulnerabilities, while supporting the development of context-specific antifibrotic interventions.