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-to-myofibroblast 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.