Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 206-214 http://medscipublisher.com/index.php/cge 208 are only present on solid tumors. Unlike blood cancers (for instance, CD19 mainly appears on cancer cells), the antigens of most solid tumors also exist in small amounts in normal tissues. This situation of antigen overlap increases the risk of accidental injury to normal tissues. CAR-T cells may attack healthy cells, causing severe and even life-threatening side effects (Yan et al., 2023; Tony et al., 2025). In addition, due to the different expression of antigens within the same tumor or among different patients, some cancer cells cannot be recognized, making it difficult to completely eliminate the tumor and eventually causing disease recurrence (Dagar et al., 2023; Guzman et al., 2023; Khan et al., 2025). To address these issues, researchers are designing new types of CAR-T cells, such as CAR-T cells capable of targeting multiple targets or those with logical control. Before these new CAR-T cells are activated, they need to recognize two or more antigens simultaneously. This can improve the accuracy of recognition and also reduce toxic side effects. But at present, it is still very difficult to find the ideal combination of antigens. Meanwhile, tumor cells may evade the action of CAR-T cells by reducing or removing target antigens. This requires continuous optimization of antigen selection and CAR design (Rodríguez-García et al., 2020; Sorkhabi et al., 2023; Chen et al., 2024). 3.2 Tumor microenvironment inhibition The microenvironment (TME) within solid tumors is highly immunosuppressive, severely limiting the efficacy of CAR-T cells. Among them, regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages, etc. will release inhibitory cytokines (such as TGF-β, IL-10), hindering the activation and proliferation of CAR-T cells (Figure 1) (Fonkoua et al., 2022; Sorkhabi et al., 2023; Ai et al., 2024). Meanwhile, the TME is usually hypoxic, acidic and nutritionally deficient, all of which can weaken the metabolism and function of T cells (Marofi et al., 2021; Maalej et al., 2023; Chen et al., 2024). Figure 1 CAR-T structure modification to enhance killing potential (Adopted from Ai et al., 2024) Physical obstacles such as dense and thick extracellular matrix and abnormal vascular structure can also prevent CAR-T cells from entering tumor tissues and affect their activity in tumor tissues. These factors together create an unfavorable environment for treatment, not only restricting the contact between CAR-T cells and tumors, but also accelerating the process of CAR-T cell function weakening and loss of efficacy. The current methods for dealing with this microenvironment include: modifying CAR-T cells to secrete inflammatory factors, resist inhibitory
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