Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 206-214 http://medscipublisher.com/index.php/cge 207 2 An Overview of the Development of CAR-T Cell Therapy 2.1 Structure and evolution Since its emergence, the structure of chimeric antigen receptor (CAR) T-cell therapy has undergone significant changes. The first-generation CAR was composed of a single-stranded variable fragment (scFv) for recognizing antigens and connecting to the CD3ζ signaling region to provide an initial activation signal, but its duration and effect were not satisfactory. The second-generation CAR incorporates a single co-stimulatory region (such as CD28 or 4-1BB), significantly enhancing the proliferation, survival and tumor clearance ability of T cells, laying an important foundation for the treatment of blood cancers (Marofi et al., 2021; Chen et al., 2024; Khan et al., 2025). The subsequent generations of cars have all been continuously improved on the basis of the previous generation. The third-generation CAR combines multiple auxiliary stimulus structures, enhancing the activity and continuous functioning ability of T cells. The fourth-generation "armored" CAR has been modified to secrete cytokines or resist immunosuppressive effects, thus performing better in complex tumor environments. The fifth-generation CAR incorporates components of cytokine receptor signaling, which can more accurately regulate the activation and reproduction of T cells and enhance their adaptability in the immunosuppressive environment of solid tumors (Chen et al., 2024; Li, 2024). The progress of research indicates that people have gained a deeper understanding of T cells and tumor immunity. The design of the new generation of cars should strive to address issues such as multiple antigens and the decline in T cell function (Wagner et al., 2020; Albelda, 2023; Ai et al., 2024). 2.2 Successful experience CAR-T cell therapy has a good therapeutic effect in hematological malignancies. In the treatment of B-cell acute lymphoblastic leukemia targeting CD19, diffuse large B-cell lymphoma, and multiple myeloma targeting BCMA, even if patients do not respond well to conventional treatments, CAR-T therapy can still bring relatively good therapeutic effects and help control the condition. These good results are mainly due to the relatively stable target antigens on the surface of tumor cells, making it easier for CAR-T cells to find and eliminate cancer cells in the blood environment (Chen et al., 2024; Khan et al., 2025). The FDA-approved related products, such as Kymriah and Yescarta for the treatment of CD19-positive cancers, and idecabtagene vicleucel for the treatment of BCMA-positive myeloma, all demonstrate the clinical value of this treatment strategy. These treatment methods have redefined the standards for personalized tumor treatment, demonstrating that even if other treatments are ineffective, the modified T cells can still achieve long-term disease control (Wagner et al., 2020; Dagar et al., 2023). The experience summarized from these successful cases provides an important reference for the expansion of CAR-T technology to the research of solid tumors. 2.3 Limitations and implications Although CAR-T performs well in hematological malignancies, its application in solid tumors still faces many difficulties. The main problems include the lack of highly specific tumor antigens, the diversity of antigen expression, and the existence of inhibitory tumor microenvironments, all of which will affect the recognition, entry and sustained action of CAR-T cells on tumors (Chen et al., 2024; Khan et al., 2025). In addition, safety risks such as off-target toxicity and cytokine release syndrome remain difficult issues that need to be taken seriously. Based on the clinical experience in treating blood diseases, it is very important to select the appropriate antigen, ensure that T cells can increase effectively, and handle the side effects that occur properly. For solid tumors, to address issues such as interstitial blockage, hypoxia, and immunosuppression, it is necessary to design more advanced CAR structures, improve the methods for recognizing antigens, and explore the path of combined therapy. These practices are driving the development of more precise CAR-T cell products and new clinical protocols, with the aim of benefiting more cancer patients (Wagner et al., 2020; Ai et al., 2024; Tony et al., 2025). 3 Major Bottlenecks of CAR-T Cell therapy for Solid Tumors 3.1 Target limitation One of the main challenges of CAR-T therapy in treating solid tumors is the inability to recognize antigens that
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