Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 206-214 http://medscipublisher.com/index.php/cge 206 Systematic Review Open Access Bottlenecks and Breakthrough Pathways of CAR-T Cell Therapy in Solid Tumors ManmanLi Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding email: manman.li@hibio.org Cancer Genetics and Epigenetics, 2025, Vol.13, No.5 doi: 10.5376/cge.2025.13.0021 Received: 08 Jul., 2025 Accepted: 10 Aug., 2025 Published: 13 Sep., 2025 Copyright © 2025 Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li M.M., 2025, Bottlenecks and breakthrough pathways of CAR-T cell therapy in solid tumors, Cancer Genetics and Epigenetics, 13(5): 206-214 (doi: 10.5376/cge.2025.13.0021) Abstract This study explored the main challenges and coping strategies of CAR-T cell therapy in the treatment of solid tumors. Although this therapy has shown remarkable efficacy in hematological malignancies, it still faces many limitations in solid tumors, including the lack of tumor-specific antigens, antigen heterogeneity and immunosuppressive microenvironment, which lead to insufficient infiltration, easy depletion and poor persistence of CAR-T cells. To this end, current research is dedicated to developing multi-target and logic-gated cars, novel antigen discovery, armored CAR-T combined immune checkpoint inhibitors, and enhancing the chemotaxis, metabolic adaptation and long-term survival ability of CAR-T cells through genetic engineering. Clinical trials have observed remission in some patients, but the overall efficacy remains limited, and there are risks such as cytokine release syndrome and neurotoxicity. Future research will focus on interdisciplinary integration (such as CAR-NK, TCR-T), synthetic biology-driven intelligent controllable CAR design, and individualized precision treatment based on genomic and tumor heterogeneity, in order to promote clinical transformation and expand its application. Keywords CAR-T cell therapy; Solid tumors; Tumor microenvironment (TME); Antigen heterogeneity; Precision medicine 1 Introduction CAR-T cell therapy has achieved excellent results in the treatment of hematological malignancies by modifying T cells to carry chimeric antigen receptors capable of recognizing tumor antigens. The FDA-approved CAR-T therapy related to CD19 and BCMA has shown good therapeutic effects in patients with B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma and multiple myeloma. Even for patients who have no effect with traditional methods, significant improvement in their condition can be observed (Dagar et al., 2023; Khan et al., 2025). This success is mainly due to the relatively uniform distribution of target antigens in hematological malignancies, which makes it easier for CAR-T cells to locate and eliminate cancer cells. CAR-T therapy has become an important breakthrough in this field (Wagner et al., 2020; Chen et al., 2024). The application of CAR-T therapy in the treatment of solid tumors still faces many difficulties. The main difficulties include the absence of highly specific tumor antigens, different antigen expression conditions, and the possibility of targeting non-tumor tissues, which can lead CAR-T cells to attack normal tissues. In addition, the tumor microenvironment with immunosuppressive effects, physical obstacles, and the insufficient number of T cells entering the tumor also greatly limit the therapeutic effect (Knochelmann et al., 2018; Khan et al., 2025). Current early clinical trials have shown that the therapeutic effect of CAR-T therapy in solid tumors is relatively limited, unstable, and there are obvious safety issues, such as cytokine release syndrome and neurotoxicity (Marofi et al., 2021; Ai et al., 2024; Tony et al., 2025). This study will explore how to expand the application scope of CAR-T cell therapy in patients with solid tumors through precise tumor treatment strategies, and systematically analyze the key issues therein. The key contents include the design of the new-generation CAR structure, the screening of tumor-specific antigens, the implementation of combined treatment strategies, and the regulatory mechanism of the tumor microenvironment. This study aims to provide theoretical and practical support for improving the sustained efficacy, safety and application scope of CAR-T therapy by comprehensively evaluating the existing progress and challenges in these aspects, and to promote the establishment of a more effective and personalized cancer immunotherapy system.
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