Adipose-derived therapeutics for radiation-induced injury and fibrosis: mechanistic and preclinical evidence

Abstract Background Radiotherapy (RT) is an essential component of modern cancer treatment but often injures adjacent healthy tissues, leading to acute radiation dermatitis and chronic radiation-induced fibrosis (RIF), a progressive condition characterized by persistent inflammation, vascular rarefaction, excessive extracellular matrix (ECM) deposition, and impaired tissue regeneration. Conventional reconstructive approaches may restore coverage or contour but do not address the underlying pathophysiological mechanisms that sustain fibrosis. Consequently, increasing attention has focused on regenerative strategies to mitigate RT-induced sequelae. Main body Adipose tissue has emerged as a clinically accessible and biologically versatile source of regenerative therapeutics, including stromal vascular fraction (SVF), adipose-derived mesenchymal stromal cells (AD-MSCs), cell-free secretome and extracellular vesicles (EVs), and decellularized adipose matrix (DAM). In this narrative review, we synthesize current mechanistic insights into radiation-induced tissue injury and fibrosis, and integrate preclinical evidence evaluating adipose-derived therapeutics across preventive, early, and late intervention windows. Available data suggest that prophylactic DAM may precondition the tissue and attenuate subsequent injury; early administration of SVF, AD-MSCs, or EVs is associated with reduced apoptosis, attenuated inflammatory responses, and improved endothelial and vascular parameters; and late-stage interventions such as cell-assisted lipotransfer or cell/SVF grafting may mitigate established fibrosis, promote ECM remodeling and vascular repair, and improve functional outcomes. Mechanistically, these therapeutics appear to act through coordinated immunomodulation, promotion of angiogenesis, attenuation of cell death, fibroblast reprogramming, and ECM remodeling. Recent evidence further highlights the potential importance of defined AD-MSC subpopulations such as CD74⁺ and CD146⁺ cells, and the possible reparative contribution of apoptotic MSCs in matrix remodeling. However, substantial heterogeneity in irradiation models, dosing regimens, therapeutic preparation, and outcome measures limits direct comparisons across studies. Many proposed mechanisms were based on associative marker changes and require causal validation. In addition, long-term oncologic safety and regulatory frameworks remain critical considerations for clinical translation. Conclusions Collectively, preclinical findings support the potential of adipose-derived therapeutics in mitigating radiation-induced injury and fibrosis. Standardization of product characterization, rigorous safety evaluation, and mechanistically informed clinical trial design will be essential to advance these promising therapies toward responsible and effective clinical applications. Clinical trial number Not applicable.