Therapeutic role of intercellular communication in keloids and hypertrophic scars and possible mechanisms

Keloids and hypertrophic scars stem from dysregulated wound healing, characterized by persistent inflammation, abnormal fibroblast activation, and excessive extracellular matrix (ECM) deposition. These pathological scars affect a large population worldwide and remain clinically challenging owing to high recurrence rates and limited efficacy of current therapies, primarily targeting downstream collagen accumulation rather than upstream drivers. In this review, the focus was on communication networks among different cell types in the scar tissue, elucidating their roles in scar formation and treatment, and summarizing current communication-based therapeutic strategies. Recent developments in single-cell and spatial transcriptomics revealed that pathological scarring is sustained by dysregulated intercellular communication among macrophages, fibroblasts, T cells, endothelial cells, Schwann cells, keratinocytes, and melanocytes. These interactions converge into fibrotic communication loops involving key mediators, including SPP1, CD44, IGFBP5, and TGF-β pathways, forming self-reinforcing cellular circuits maintaining fibrosis. Furthermore, exosomes propagate fibrotic signaling by delivering regulatory miRNAs and proteins; however, engineered exosomes and miRNA-based approaches (e.g., miR-29a-3p delivery) demonstrate emerging therapeutic potential. Understanding these communication networks reinforces the need for phase-specific therapeutic strategies, including early immune modulation, mid-stage inhibition of fibroblast–vascular crosstalk, late-stage ECM remodeling, and exosome-based interventions. Targeting upstream intercellular communication rather than isolated downstream fibrosis offers a promising precision-therapy framework for improving outcomes in pathological scar management.