{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:16:14Z","timestamp":1789154174039,"version":"build-2803163510"},"reference-count":69,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Hormone-receptor-positive (HR+)\/HER2-negative (HER2\u2212) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+\/HER2\u2212 BC patients, focusing on potential biomarkers of response and resistance to these drugs. Methods: We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II\/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+\/HER2\u2212 BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Results: Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4\/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Discussion: Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+\/HER2\u2212 BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+\/HER2\u2212 breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients.<\/jats:p>","DOI":"10.3390\/cancers17172940","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T08:40:15Z","timestamp":1757407215000},"page":"2940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unlocking the Potential of Immune Checkpoint Inhibitors in HR+\/HER2\u2212 Breast Cancer: A Systematic Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6147-9655","authenticated-orcid":false,"given":"Giuseppe","family":"Di Grazia","sequence":"first","affiliation":[{"name":"School of Specialization in Medical Oncology, Department of Human Pathology \u201cG. Barresi\u201d, Azienda Ospedaliera Universitaria Policlinico \u201cG. Martino\u201d, University of Messina, Via Consolare Valeria N. 1, Gazzi, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6992-301X","authenticated-orcid":false,"given":"Arianna","family":"Dri","sequence":"additional","affiliation":[{"name":"Department of Medicine (DMED), University of Udine, 33100 Udine, Italy"},{"name":"Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico (CRO) di Aviano, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Grieco","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2623-4705","authenticated-orcid":false,"given":"Michela","family":"Palleschi","sequence":"additional","affiliation":[{"name":"Medical Oncology, Breast & GYN Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5062-2914","authenticated-orcid":false,"given":"Federica","family":"Martorana","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica \u201cF. Latteri\u201d-lato nord-p. 9 via Santa Sofia, 89, 95123 Catania, Italy"},{"name":"Humanitas Istituto Clinico Catanese, University Oncology Department, Contrada Cubba Marletta, 11, Misterbianco, 95045 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Barchiesi","sequence":"additional","affiliation":[{"name":"UOC Oncologia A, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4074-2530","authenticated-orcid":false,"given":"Grazia","family":"Arpino","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1158-4630","authenticated-orcid":false,"given":"Carmine","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Scuola Superiore Meridionale, Via Mezzocannone, 4, 80134 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelino","family":"De Laurentiis","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Tumori IRCCS Fondazione G Pascale, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9546-5841","authenticated-orcid":false,"given":"Lucia","family":"Del Mastro","sequence":"additional","affiliation":[{"name":"IRCSS Ospedale Policlinico San Martino, UO Breast Unit, 16121 Genoa, Italy"},{"name":"Department of Internal Medicine and Medical Specialties (DIM), Universit\u00e0 di Genova, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-4938","authenticated-orcid":false,"given":"Fabio","family":"Puglisi","sequence":"additional","affiliation":[{"name":"Department of Medicine (DMED), University of Udine, 33100 Udine, Italy"},{"name":"Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico (CRO) di Aviano, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5943-6066","authenticated-orcid":false,"given":"Paolo","family":"Vigneri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica \u201cF. Latteri\u201d-lato nord-p. 9 via Santa Sofia, 89, 95123 Catania, Italy"},{"name":"Humanitas Istituto Clinico Catanese, University Oncology Department, Contrada Cubba Marletta, 11, Misterbianco, 95045 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Giuliano","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","first-page":"14","article-title":"The breast cancer tumor microenvironment and precision medicine: Immunogenicity and conditions favoring response to immunotherapy","volume":"4","author":"Nicolini","year":"2024","journal-title":"J. Natl. 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