{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:47:13Z","timestamp":1789429633728,"version":"build-2803163510"},"reference-count":137,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Messenger RNA (mRNA) vaccines are emerging as promising tools capable of reshaping how cancer interacts with the immune system and responds to immunotherapy. These vaccines not only act as platforms for antigen delivery but can also influence the tumor microenvironment (TME), fostering a shift from immunologically \u201ccold\u2019\u2019 conditions toward \u201chotter\u2019\u2019 and treatment-responsive states. In melanoma, this capability has been found to enhance the efficacy of the immune checkpoint inhibitors (ICIs), as mRNA-based priming can provide the robust antitumor activation needed for more effective checkpoint blockade. Early clinical studies with personalized or off-the-shelf vaccines showed benefits in patients with high-risk resected melanoma or refractory to PD-1 inhibition. Combining mRNA vaccines with ICIs, along with other immunomodulatory strategies, may be helpful to overcome resistance arising from the TME and achieve more durable clinical benefits. Besides these advances, computational and in silico modeling are providing new insights into how mRNA vaccines modulate the TME, helping to identify factors such as antigen-presenting cell (APC) density, CD8+ T-cell infiltration, and macrophage polarization that may predict treatment success and guide personalized strategies. Together, these developments indicate that combining mRNA vaccination with ICIs, supported by computational tools, may improve clinical outcomes in melanoma and, potentially, in selected tumor types with favorable immunological features, although important biological constraints limit direct extrapolation to less immunogenic malignancies.<\/jats:p>","DOI":"10.3390\/cells15110986","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["How Deeply Can mRNA Vaccines Affect the Responsiveness to Immune Checkpoint Inhibitors Through Changes in the Tumor Microenvironment? Evidence from Melanoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Ivana","family":"Persico","sequence":"first","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Doro","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9844-1052","authenticated-orcid":false,"given":"Laura","family":"Frogheri","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Sini","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Battista","family":"Maestrale","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2497-1541","authenticated-orcid":false,"given":"Antonella","family":"Manca","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-5313","authenticated-orcid":false,"given":"Domenico","family":"Mallardo","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Tumori (INT), Fondazione \u201cGiovanni Pascale\u201d, 80040 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Antonio","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Tumori (INT), Fondazione \u201cGiovanni Pascale\u201d, 80040 Naples, Italy"},{"name":"Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80040 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4350-2276","authenticated-orcid":false,"given":"Giuseppe","family":"Palmieri","sequence":"additional","affiliation":[{"name":"Unit of Cancer Genetics, Institute of Genetics and Biomedical Research (IRGB), National Research Council (CNR), 07100 Sassari, Italy"},{"name":"Immuno-Oncology & Targeted Cancer Biotherapies, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.2217\/nnm-2016-0275","article-title":"Translating nanoparticulate-personalized cancer vaccines into clinical applications: Case study with RNA-lipoplexes for the treatment of melanoma","volume":"11","author":"Grabbe","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/s41568-023-00565-7","article-title":"The journey from melanocytes to melanoma","volume":"23","author":"Centeno","year":"2023","journal-title":"Nat. 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