{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:07:29Z","timestamp":1779084449681,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of selected hematologic malignancies, particularly relapsed or refractory large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, currently approved CAR-T strategies largely rely on lineage-associated or differentiation antigens, such as CD19 or BCMA, and therefore do not selectively distinguish malignant B cells from their normal counterparts. This limitation contributes to on-target, off-tumor toxicity, including B-cell aplasia, hypogammaglobulinemia, infectious complications, and prolonged immune dysfunction. In addition, CAR-T therapy remains associated with cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, manufacturing complexity, and variable efficacy across disease entities, particularly in chronic lymphocytic leukemia. Chimeric autoantibody receptor T-cell (CAAR-T) therapy represents a conceptually distinct approach in which engineered T cells are designed to recognize disease-defining immunoglobulin structures, including surface immunoglobulin or B-cell receptor idiotypes. This strategy has been most extensively explored in autoimmune diseases, where CAAR-T cells can selectively eliminate autoreactive B-cell populations while sparing the broader B-cell compartment. Its application in B-cell malignancies remains largely hypothetical, but the biological principle is attractive because many B-cell neoplasms are defined by clonotypic immunoglobulin rearrangements. In this review, we provide a disease-specific and translationally oriented assessment of idiotype-directed CAAR-T therapy in B-cell malignancies. We summarize the current evidence supporting CAAR-T biology, critically evaluate its potential in chronic lymphocytic leukemia, indolent lymphomas, multiple myeloma, and minimal residual disease, and discuss key biological, economic, manufacturing, and regulatory barriers. At present, CAAR-T should not be viewed as a near-term replacement for approved CAR-T therapies, but rather as a hypothesis-generating precision platform requiring rigorous disease-specific validation.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1842236","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:39:57Z","timestamp":1779082797000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From CAR-T to CAAR-T: redefining targeting strategies in B-cell malignancies through idiotype-directed cellular therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Tomasz","family":"Buczek","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Wroclaw Medical University Branch in Walbrzych","place":["Walbrzych, Poland"]},{"name":"Oncology Support Centre for Clinical Trials, Alfred Sokolowski Specialist Hospital in Walbrzych","place":["Walbrzych, 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