Beyond rejection: engineering immune responses to redefine skin graft survival

Skin grafting remains a fundamental reconstructive technique in reconstructive and dermatologic surgery for restoring skin integrity following burns, trauma, chronic ulcers, and excision of malignancies. However, a graft survival rate is determined by multiple factors and by a delicate balance between inflammatory and reparative immune system processes. Controlled inflammation promotes wound healing while excessive or prolonged immune activation has the potential to result in cytotoxicity and complement activation which will eventually lead to graft rejection. Early rejection is driven by antibody-meditated complement cascade and innate effector cells like macrophages and natural killer (NK) cells while long-term graft rejection often results from T cell-mediated cytotoxicity and alloantibody production. Molecular mediators such as reacting oxygen species, pro-inflammatory cytokines, and matrix metalloproteinases (MMP) further amplify tissue injury and prevent healing. Current immunosuppressive therapies like calcineurin inhibitors and different corticosteroids reduce rejection to a certain level and are limited by systemic toxicity and impaired wound healing. Emerging strategies including bioengineered scaffolds, localized cytokine inhibitors, and stem cell-derived factors offer targeted immunomodulation to enhance graft tolerance and long-term survival. Despite promising preclinical data, translation into humans and application of the new emerging therapies remain constrained by species differences, ethical considerations, and variability in patient immune profiles. Advancing humanized models, biomaterial-based therapies, and precision immunotherapy will be pivotal in optimizing graft outcomes. This review aims to highlight how strategic modulation of inflammatory pathways can predict better graft outcomes and pave the way for next-generation regenerative therapies.