{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:58:19Z","timestamp":1791295099820,"version":"4.1.0"},"reference-count":194,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pleural mesothelioma (PM) is a rare and aggressive cancer with limited treatment options and poor prognosis. Unlike other thoracic cancers responding well to immunotherapy, PM typically lacks key predictive biomarkers such as Programmed Death-Ligand 1 (PD-L1) tumor expression. Nonetheless, immune checkpoint inhibitors (ICIs) have shown clinical activity in PM, particularly in non-epithelioid subtypes. However, only a subset of patients benefits from this approach, and resistance remains a major challenge. A growing body of evidence suggests that tumor microenvironment (TME) plays a central role in shaping this resistance. In PM, the TME is notably immunosuppressive, dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These elements act as a shield against immune activation, limiting the efficacy of ICIs. Novel therapeutic strategies aimed at depleting or modulating suppressive immune populations within the TME are emerging as promising avenues to overcome resistance and enhance the effectiveness of ICIs. In this narrative review, we examine the unique features of the TME in PM, its role in immunotherapy resistance, and emerging strategies aimed at harnessing or remodeling the TME to improve patient outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1814514","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:18:46Z","timestamp":1791292726000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming the tumor microenvironment in mesothelioma: from immune suppression to therapeutic opportunity"],"prefix":"10.3389","volume":"17","author":[{"given":"Luigi","family":"Cerbone","sequence":"first","affiliation":[{"name":"SSD Mesotelioma, Melanoma e Tumori Rari, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]},{"name":"DISSTE - Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Universit\u00e0 del Piemonte Orientale","place":["Vercelli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Garau","sequence":"additional","affiliation":[{"name":"SSD Mesotelioma, Melanoma e Tumori Rari, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]},{"name":"SC Infrastruttura Ricerca Formazione e Innovazione, Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Balossino","sequence":"additional","affiliation":[{"name":"UO Tumori Polmonari, Oncologia Medica, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Martinotti","sequence":"additional","affiliation":[{"name":"DiSIT- Dipartimento di Scienze e Innovazione Tecnologica, Universit\u00e0 del Piemonte Orientale","place":["Alessandria, Italy"]},{"name":"SSD Laboratori di Ricerca, Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elia","family":"Ranzato","sequence":"additional","affiliation":[{"name":"DiSIT- Dipartimento di Scienze e Innovazione Tecnologica, Universit\u00e0 del Piemonte Orientale","place":["Alessandria, Italy"]},{"name":"SSD Laboratori di Ricerca, Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Genova","sequence":"additional","affiliation":[{"name":"UOC Clinica di Oncologia Medica, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]},{"name":"DIMI - Dipartimento di Medicina Interna e Specialit\u00e0 Mediche, Universit\u00e0 degli Studi di Genova","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rigo","sequence":"additional","affiliation":[{"name":"UOC Bioterapie, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Meda","sequence":"additional","affiliation":[{"name":"SC Chirurgia Toracica, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Ravera","sequence":"additional","affiliation":[{"name":"SC Malattie Apparato Respiratorio, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector Jos\u00e8 Soto","family":"Parra","sequence":"additional","affiliation":[{"name":"UO Oncologia Medica, Azienda Ospedaliero Universitaria Policlinico \u201cG. 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