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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)\u2014endogenous molecules that signal cellular stress and damage\u2014contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group Box 1 (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs\u2014including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin\u2014contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways.<\/jats:p>","DOI":"10.3390\/ijms27177859","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T14:35:29Z","timestamp":1788359729000},"page":"7859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1461-4034","authenticated-orcid":false,"given":"Annamaria","family":"Molinario","sequence":"first","affiliation":[{"name":"Comprehensive Cancer Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9505-8157","authenticated-orcid":false,"given":"Francesca","family":"Caprioglio","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1148-3361","authenticated-orcid":false,"given":"Angela A.","family":"Rilievo","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5329-6445","authenticated-orcid":false,"given":"Marco E.","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1271-8998","authenticated-orcid":false,"given":"Rosanna","family":"Mezzapelle","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.annonc.2021.11.005","article-title":"Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"33","author":"Popat","year":"2022","journal-title":"Ann. 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