{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:54:47Z","timestamp":1789606487125,"version":"build-2803163510"},"reference-count":192,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"AIRC","doi-asserted-by":"publisher","award":["IG-20148"],"award-info":[{"award-number":["IG-20148"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"AIRC","doi-asserted-by":"publisher","award":["ERC-2021-SyG 951329"],"award-info":[{"award-number":["ERC-2021-SyG 951329"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"EU","doi-asserted-by":"publisher","award":["IG-20148"],"award-info":[{"award-number":["IG-20148"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"EU","doi-asserted-by":"publisher","award":["ERC-2021-SyG 951329"],"award-info":[{"award-number":["ERC-2021-SyG 951329"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response.<\/jats:p>","DOI":"10.3390\/ijms232214255","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T03:29:50Z","timestamp":1668742190000},"page":"14255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs)"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-2298","authenticated-orcid":false,"given":"Chiara","family":"Cassioli","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-6955","authenticated-orcid":false,"given":"Laura","family":"Patrussi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Valitutti","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1037, Centre de Recherche en Canc\u00e9rologie de Toulouse (CRCT), Universit\u00e9 de Toulouse III-Paul Sabatier, 31037 Toulouse, France"},{"name":"Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4414-6744","authenticated-orcid":false,"given":"Cosima T.","family":"Baldari","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A Guide to Cancer Immunotherapy: From T Cell Basic Science to Clinical Practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. 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