Regulation of Tissue Regeneration by Immune Microenvironment–Fibroblast Interactions

Tissue regeneration is a highly complex and dynamic process critically influenced by the immune microenvironment and its multifaceted interactions with fibroblasts. Traditionally regarded as structural cells responsible for extracellular matrix (ECM) production, fibroblasts have recently emerged as active regulators orchestrating immune responses and tissue repair. This review focuses on the reciprocal crosstalk between fibroblasts and key immune components, including macrophages, T cells, ECM, local pH, and signaling proteins. These interactions coordinate the initiation and resolution phases of inflammation, regulating fibroblast migration, proliferation, differentiation, and ECM deposition, which collectively determine the efficiency and quality of tissue repair. Special attention is given to the dynamic modulation of the immune microenvironment that governs fibroblast behavior during injury and regeneration. Finally, recent therapeutic strategies targeting this crosstalk-from molecular inhibitors to cell-based therapies-are discussed, highlighting emerging avenues for enhancing regenerative outcomes and mitigating fibrotic diseases. This integrated perspective positions fibroblast-immune interactions as a promising frontier in regenerative medicine, offering new opportunities for targeted tissue repair and control of chronic inflammation.