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Summarizes current therapeutic strategies and highlights future research directions to improve clinical durability and potency across hematologic malignancies. 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M.)  \n†These authors contributed equally to this work.  \nAs pioneering immunotherapy approaches, chimeric antigen receptor T cell (CAR-T) and natural killer cell (CAR-NK) therapies have shown notable clinical effectiveness when addressing different kinds of hematologic malignancies. For example, the application and efficacy of CAR-T cell therapy in acute lymphocytic leukemia, large B cell lymphoma, mantle cell lymphoma, and multiple myeloma have been widely recognized. In addition, the safety and feasibility of CAR-NK therapy when used to treat refractory/ recurrent large B cell lymphoma have been verified. In particular, CD19-targeted CAR-T cell therapy has achieved marked efficacy and breakthrough progress in treating relapsed and refractory B cell leukemia and lymphoma. Although CAR-T cell therapy has achieved significant effectiveness in treating these diseases, patients still face challenges, including primary resistance and secondary recurrence after treatment. The complex mechanisms of resistance and recurrence involve multiple factors, such as target cells, CAR cell characteristics, and immune suppression conditions. This review examines resistance and recurrence mechanisms in CAR-T and CAR-NK therapies while exploring current therapeutic strategies and future research directions.  \nCitation: Wang Y, Shao W, Mao J, Ye Q. Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside. Research 2026;9:Article 1068. [https://doi](https://doi). org/10.34133/research.1068  \nSubmitted 22 October 2025  \nRevised 9 December 2025  \nAccepted 10 December 2025 Published 5 January 2026  \nCopyright © 2026 Yuhe Wang etal. Exclusive licensee Science and Technology Review Publishing House. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License (CC BY 4 .0) .  \nIntroduction  \nChimeric antigen receptor (CAR) T cell therapy stands as a revolutionary cancer immunotherapy approach. Through genetic engineering techniques, T cells are modified to acquire the unique ability to precisely recognize and target specific antigens, thereby attacking target cells. When a CAR binds to a target antigen, it rapidly activates immune cells that carry the receptor, prompting them to release toxins to kill abnormal cells and secrete signaling molecules to recruit other immune components to participate in the response while supporting their own proliferation [1] . While the success of CAR-T cells in hematologic malignancies and solid tumors is well-established, their application is now expanding into areas such as autoimmune diseases (AIDs), where they enable the profound and sustained depletion of pathogenic B cells [2] . However, CAR-T cell therapy still faces challenges, including severe side effects, a long preparation cycle, high costs, and limited efficacy for solid tumors [3]. These limitations have spurred the development of alternative cellular platforms, most notably chimeric antigen receptor natural killer (CAR-NK) cells [4] . CAR-NK cells offera number of advantages, including inherent antitumor activity,  \nbeing unre","cbCaibpDvSflFBxC","https://ap.wps.com/l/cbCaibpDvSflFBxC","pdf",4815870,17,"English","# Introduction\n## Current Status of CAR-T and CAR-NK Cell Therapy\n### Biological Basis of CAR-T/CAR-NK Cells","[{\"question\":\"What challenges cause resistance and relapse after CAR-T and CAR-NK therapies?\",\"answer\":\"Patients face primary resistance and secondary recurrence. Mechanisms involve multiple factors, including target cell features, CAR cell characteristics, and immune suppression within the tumor microenvironment.\"},{\"question\":\"Which three key aspects does the review organize to address resistance mechanisms?\",\"answer\":\"The review covers resistance mechanisms and strategies through three aspects: target cell factors, CAR-T cell factors, and immunosuppressive environment-related factors.\"},{\"question\":\"Why do patients still relapse even after clinically effective CAR-T therapy?\",\"answer\":\"Despite improvements and recognized clinical effectiveness, therapeutic durability remains a major concern. Long-term follow-up shows many patients eventually relapse with antigen-positive or antigen-negative disease.\"}]","Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies - From Bench to Bedside | PDF",1790682857,43]