Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 206-214 http://medscipublisher.com/index.php/cge 209 signals, or produce enzymes capable of decomposing extracellular matrix (Hou et al. 2021; Dagar et al., 2023; Khan et al., 2025). 3.3 T cell dysfunction CAR-T cells face multiple functional difficulties in the treatment of solid tumors: they are difficult to migrate to the tumor area, difficult to cross the physicochemical barrier and immune barrier, and prone to rapid exhaustion. Unlike malignant cells in hematological malignancies that are easily accessible, solid tumors require CAR-T cells to cross complex tissue structures and resist inhibitory signals before reaching the target site (Marofi et al., 2021; Maalej et al., 2023; Dagar et al., 2023; Khan et al., 2025). After CAR-T cells enter the tumor, they often gradually lose their function due to continuous antigen stimulation, manifested as reduced cytokine secretion, decreased killing ability and increased inhibitory receptors. This weakened function, coupled with the lack of supporting factors and long-term immunosuppression, shortens the survival time of CAR-T cells and makes it difficult to maintain the anti-tumor effect. The coping methods include optimizing the signal structure of CAR, combining the use of checkpoint inhibitors, or enhancing the metabolic level of T cells and their ability to resist functional decline through genetic modification (Sorkhabi et al., 2023; Ai et al., 2024; Chen et al., 2024). 4 Breakthrough Approaches and Cutting-edge Strategies for CAR-T Cell Therapy 4.1 Design exploration of novel solid tumor antigens and multi-target cars Researchers are developing CAR-T cells capable of recognizing multiple antigens to address the issue of uneven antigen distribution and the lack of truly specific targets in solid tumors. Bispecific or tandem cars can simultaneously bind to two or more antigens, which can reduce tumor escape caused by antigen absence and expand the range of tumor cell recognition. By simultaneously locking multiple tumor-related antigens, these novel CAR structures can more accurately identify tumors and reduce accidental damage to normal tissues-which is a very important safety issue in the treatment of solid tumors (Figure 2) (Dagar et al., 2023; Sorkhabi et al., 2023; Yan et al., 2023; Chen et al., 2024). Meanwhile, by means of high-throughput screening, single-cell sequencing and artificial intelligence, scientists are striving to search for new solid tumor antigens, including tumor-specific antigens (TSA) and neoantigens (Yan et al., 2023). The discovery of neoantigens specific to tumor cells is conducive to the development of safer and more potent CAR-T therapies, benefiting more patients with solid tumors (Guzman et al., 2023; Khan et al., 2025). 4.2 Armored CAR-T and its combined application with immune checkpoint inhibitors The immunosuppressive characteristics of the tumor microenvironment (TME) are the main difficulty faced by CAR-T in the treatment of solid tumors. The modified armored CAR-T cells can secrete pro-inflammatory cytokines (such as IL-12, IL-18) or express receptors that can block inhibitory signals, thereby enhancing the viability and survival ability of T cells in the TME (Fonkoua et al., 2022; Sorkhabi et al., 2023). These modifications enable CAR-T cells to resist the influence of regulatory cells and inhibitory factors, enhancing their tumor-clearing effect (Marofi et al., 2021; Chen et al., 2024). The combination of CAR-T therapy and immune checkpoint suppressor drugs (such as anti-PD-1 and anti-CTLA-4 antibodies). This combined approach can reactivate T cells that have lost their function and also interfere with the immunosuppressive pathways in the TME. Thus, CAR-T cells can survive for a longer time and enhance their function at the same time (Fonkoua et al., 2022). Early clinical and preclinical research results have shown that this combination therapy can have a synergistic enhanced anti-cancer effect on solid tumors (Khan et al., 2025; Lou and Xu, 2025). 4.3 Improve chemotaxis, metabolism and persistence through genetic engineering Genetic engineering is used to enhance the migration, metabolic adaptation and long-term persistence of CAR-T cells in solid tumors. By introducing receptors that match the chemokines released by tumors (such as CXCR2,
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