{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:13:21Z","timestamp":1786461201675,"version":"build-2736575974"},"reference-count":99,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Molecular Bases of Disease Dissemination in Lymphoid Malignancies to Optimize Curative Ther-apeutic Strategies","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"the AGING Project\u2014Department of Excellence\u2014DIMET, Universit\u00e0 del Piemonte Orientale, Novara, Italy"},{"DOI":"10.13039\/501100003196","name":"Italian MoH","doi-asserted-by":"publisher","award":["PNRR-MAD-2022-12375673"],"award-info":[{"award-number":["PNRR-MAD-2022-12375673"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AIL Novara VCO ODV"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>CD20 \u00d7 CD3 bispecific antibodies (BsAbs) have emerged as a meaningful therapeutic option for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), redirecting endogenous T cells against malignant B cells independently of major histocompatibility complex-mediated antigen presentation, and have received regulatory approval after at least two prior lines of therapy. However, a substantial proportion of patients experience primary resistance or early relapse, underscoring the need to characterize the underlying biological mechanisms, which are the focus of this review. Several tumor-intrinsic determinants of resistance have been identified, including CD20 loss driven by MS4A1 mutations, alternative splicing, and gene deletion, as well as genomic reprogramming involving TP53, MYC, and NOTCH1 alterations. T-cell dysfunction represents another critical resistance domain, encompassing inadequate intratumoral cytotoxic CD8+ T-cell infiltration, expansion of immunosuppressive regulatory and follicular helper T cells, progressive exhaustion with upregulation of PD-1, LAG-3, TIM-3, and TIGIT, and impaired T-cell fitness from prior treatment exposure. Microenvironmental barriers, including checkpoint ligand upregulation, PD-L1-enriched extracellular vesicles, spatial exclusion of effector cells from immune-cold germinal center-like niches, hypoxia, and metabolic competition, further reinforce immune escape. Emerging strategies to overcome resistance include epigenetic priming, checkpoint inhibitor combinations, 4-1BB costimulatory approaches, and next-generation multispecific antibody designs.<\/jats:p>","DOI":"10.3390\/cells15090794","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"794","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Mechanisms of Resistance to Bispecific Antibodies in Diffuse Large B-Cell Lymphoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9307-1965","authenticated-orcid":false,"given":"Nawar","family":"Maher","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4218-1917","authenticated-orcid":false,"given":"Bashar","family":"Al Deeban","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1551-8801","authenticated-orcid":false,"given":"Ndeye Marie","family":"Diop","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle","family":"Assaf","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Moia","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0389-3268","authenticated-orcid":false,"given":"Samir","family":"Mouhssine","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-0151","authenticated-orcid":false,"given":"Gianluca","family":"Gaidano","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, Alessandria and Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood.2022015851","article-title":"The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee","volume":"140","author":"Campo","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1056\/NEJMra2027612","article-title":"Diffuse Large B-Cell Lymphoma","volume":"384","author":"Sehn","year":"2021","journal-title":"N. 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