{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:02:07Z","timestamp":1784552527274,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Cancer vaccines represent the next frontier in immunotherapy, aiming to elicit long-lasting protective anti-tumor immune responses. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast cancer. Active immunization with HER2-displaying M13 bacteriophages can induce a therapeutic immune response against HER2-positive breast cancer, offering a promising alternative to trastuzumab. However, the duration of anticancer immune protection triggered by anti-HER2 phage-based vaccines is limited by tumor-immune suppressive mechanisms. Methods: In this study, two vaccination cycles with ECTM phages displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 were combined with palbociclib, a CDK4\/6 inhibitor, to enhance antitumor immunity in the clinically relevant \u039416HER2 transgenic preclinical model of breast cancer. Results: The proposed combination treatment resulted in a better and long-lasting control of tumor growth rate and multiplicity than either palbociclib or phage vaccination alone, correlating with a significantly stronger anti-HER2 humoral response (IgG2a isotype). Analysis of the tumor immune infiltrate revealed an increased presence of CD8+ T cells concomitant with a reduction in FoxP3+ regulatory T cells (Tregs) in tumors explanted from mice receiving the combination therapy. Conclusions: These preclinical results provide a rationale for the clinical translation of CDK4\/6 inhibitors combined with anti-HER2 active immunotherapies in breast cancer, as they may yield sustained antitumor responses by reverting the immunosuppressive tumor environment.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070881","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:00:17Z","timestamp":1784548817000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting CDK4\/6 in Combination with Phage-Based Anti-HER2 Vaccination Overcomes Immune Evasion and Enhances the Anticancer Response in Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8695-323X","authenticated-orcid":false,"given":"Junbiao","family":"Wang","sequence":"first","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7421-4509","authenticated-orcid":false,"given":"Alessia","family":"Lamolinara","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology, Department of Neurosciences, Imaging and Clinical Sciences, G. d\u2019Annunzio University of Chieti-Pescara, 66013 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9062-3305","authenticated-orcid":false,"given":"Daniele","family":"Tomassoni","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1780-098X","authenticated-orcid":false,"given":"Laura","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1305-5644","authenticated-orcid":false,"given":"Chiara","family":"Cossu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5037-3396","authenticated-orcid":false,"given":"Antonino","family":"Di Lorenzo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Giangrossi","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Lufrano","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"},{"name":"Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata, CONICET (Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas), 47 & 115, La Plata B1900AVW, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varshini","family":"Vaithianathan","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7351-4430","authenticated-orcid":false,"given":"Fiorenza","family":"Orlando","sequence":"additional","affiliation":[{"name":"Experimental Animal Models for Aging Unit, Scientific Technological Area, IRCCS INRCA, 60100 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Olivieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica Delle Marche, 60100 Ancona, Italy"},{"name":"Biogerontology Center and Geriatric Mouse Clinic, IRCCS INRCA, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5873-5753","authenticated-orcid":false,"given":"Serena","family":"Marcozzi","sequence":"additional","affiliation":[{"name":"Biogerontology Center and Geriatric Mouse Clinic, IRCCS INRCA, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4935-7874","authenticated-orcid":false,"given":"Daniela","family":"Beghelli","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2249-0285","authenticated-orcid":false,"given":"Barbara","family":"Belletti","sequence":"additional","affiliation":[{"name":"Molecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, National Cancer Institute, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4634-1500","authenticated-orcid":false,"given":"Augusto","family":"Amici","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4646-6741","authenticated-orcid":false,"given":"Maurizio","family":"Falconi","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4571-1060","authenticated-orcid":false,"given":"Federica","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1622954","DOI":"10.3389\/fpubh.2025.1622954","article-title":"Global burden and projections of breast cancer incidence and mortality to 2050: A comprehensive analysis of GLOBOCAN data","volume":"13","author":"Freihat","year":"2025","journal-title":"Front. 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