{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:13:14Z","timestamp":1790791994288,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Fondazione AIRC per la Ricerca sul Cancro ETS","doi-asserted-by":"publisher","award":["IG2016-18451"],"award-info":[{"award-number":["IG2016-18451"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"Fondazione AIRC per la Ricerca sul Cancro ETS","doi-asserted-by":"publisher","award":["IG2019\u201322805"],"award-info":[{"award-number":["IG2019\u201322805"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress stimuli, including drug resistance. CD99 is crucial at the intersection of normal biological processes and pathological conditions like cancer. While research indicates that CD99 may interact homotypically, there is evidence of some heterotypic ligands that align with its roles. The development of multiple anti-CD99 antibodies has shed light on its functions, particularly regarding interactions between tumor cells that overexpress CD99 and immune cells expressing the same protein within the microenvironment. Anti-CD99 antibodies effectively eliminate tumors and attract immune cells to the tumor area. Additionally, CD99 influences the expression of specific immune checkpoint molecules, such as CD47, paving the way for potential combinations of anti-CD99 with immune checkpoint inhibitors. This review explores CD99\u2019s role in normal physiology and cancer biology, focusing on how monoclonal antibodies affect CD99 expression and activity, thereby influencing cancer cells\u2019 interactions with their microenvironment. It summarizes key findings about how these changes impact cancer cell behavior and the effectiveness of treatments.<\/jats:p>","DOI":"10.3390\/biom15050632","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["CD99: A Key Regulator in Immune Response and Tumor Microenvironment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-720X","authenticated-orcid":false,"given":"Maria Cristina","family":"Manara","sequence":"first","affiliation":[{"name":"Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3756-6983","authenticated-orcid":false,"given":"Valentina","family":"Fiori","sequence":"additional","affiliation":[{"name":"Diatheva srl, 61030 Cartoceto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5496-0250","authenticated-orcid":false,"given":"Angelo","family":"Sparti","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6114-9499","authenticated-orcid":false,"given":"Katia","family":"Scotlandi","sequence":"additional","affiliation":[{"name":"Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s12079-017-0445-z","article-title":"CD99 at the crossroads of physiology and pathology","volume":"12","author":"Pasello","year":"2018","journal-title":"J. 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