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However, this paradigm alone does not fully explain disease chronicity, relapse, or the limited therapeutic responses. Evidence supports a broader conceptual framework in which vitiligo is sustained by defective immune control of dysregulated responses, coupled with impaired regeneration, resulting in persistent inflammation and failure to restore cutaneous homeostasis. Here, we reinterpret vitiligo immunopathogenesis as a disorder of failed restoration of immunological homeostasis, extending beyond classical immune activation to include defects in regulatory mechanisms that normally constrain autoreactive responses. Rather than focusing exclusively on broad immunosuppression, emerging strategies increasingly aim to restore local immune regulation, constrain pathogenic immune memory, and preserve or reconstitute melanocyte regenerative niches. Advances in cutaneous immunology and biotechnology have expanded the therapeutic landscape to include targeted cytokine and kinase inhibition, immune checkpoint modulation, pro-melanogenic and regenerative approaches, cell- and vesicle-based therapies, nucleic acid-based interventions, and advanced skin delivery systems. Accumulating knowledge supports combined and sequential treatment paradigms integrating immune modulation, induction of repigmentation, and long-term maintenance. Nevertheless, translation into routine clinical practice remains limited by cutaneous pharmacokinetic barriers, regulatory and manufacturing constraints, and the lack of long-term safety and efficacy data. Within this evolving landscape, precision medicine offers a framework for patient stratification, therapeutic timing, and rational treatment design. Importantly, many of these approaches remain in early or preclinical stages, highlighting the need for robust translational validation. On the other hand, delivery platforms based on nanotechnology emerge as potential tools capable of bridging diverse therapeutic modalities by enhancing stability, targeting, and cutaneous bioavailability. Finally, this review positions vitiligo as a disease of failed immune resolution and impaired tissue regeneration, highlighting precision immunoengineering and technological innovation as promising pathways toward more targeted, personalized, and durable disease-modifying therapies.<\/jats:p>","DOI":"10.1007\/s12016-026-09165-3","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T06:00:05Z","timestamp":1778306405000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Vitiligo as a Failure of Immune Resolution and Tissue Regeneration: From Stress Signals to Targeted Immune Modulation"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1519-3701","authenticated-orcid":false,"given":"Ana Vit\u00f3ria","family":"Pupo Silvestrini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9841-6634","authenticated-orcid":false,"given":"Jackeline Marino","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6156-3144","authenticated-orcid":false,"given":"Cristina Ribeiro","family":"de Barros Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1246-5433","authenticated-orcid":false,"given":"Maria Vit\u00f3ria","family":"Lopes Badra Bentley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"9165_CR1","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1111\/j.1365-4632.2007.03195.x","volume":"46","author":"GWM Millington","year":"2007","unstructured":"Millington GWM, Levell NJ (2007) Vitiligo: the historical curse of depigmentation. 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