Cutaneous Immune Memory: A Double-Edged Sword in Skin Repair and Fibrosis

The skin, the body's largest and most immunologically dynamic organ, functions as both a protective barrier and an active immune interface. Tissue-resident memory T cells (TRMs) are pivotal in orchestrating localized immune responses, enabling rapid antigen-specific reactions, tissue repair, and immune cell recruitment. However, dysregulated TRM activity can drive chronic inflammation and fibrosis, complicating repair processes. This review examines the dual roles of TRMs and innate immune memory in wound healing and pathogen defense, emphasizing their interplay within cutaneous immune memory. This unique memory system integrates adaptive and innate immunity to enhance skin defense and repair but can contribute to pathologies, such as chronic wounds and keloids, when dysregulated. We discuss promising interventions, including cytokine delivery, biomaterial-based scaffolds, and epigenetic modulators, to enhance healing while mitigating pathology. These strategies aim to harness cutaneous immune memory for improved outcomes in conditions such as diabetic ulcers and recurrent infections. A key challenge is balancing protective and pathological immune responses, underscoring the need for personalized, skin-targeted immunotherapies with demonstrated long-term efficacy. By synthesizing recent advances, this review highlights novel therapeutic opportunities to modulate cutaneous immune memory, addressing critical knowledge gaps to guide future research and clinical translation.