The article discusses the current challenges and strategies to overcome limitations in CAR T cell therapy, particularly in the context of solid tumors and other cancers. Key challenges include severe toxicities, poor tumor infiltration, suboptimal persistence, antigen escape, and manufacturing issues. To address these, researchers are developing innovative CAR designs, such as using MHC-dependent TCR-mimic CARs, targeting intracellular tumor-associated antigens, and incorporating cytokines or other ligands to enhance T cell activation. The article also highlights the importance of optimizing the CAR structure, including the antigen-binding domain, hinge, transmembrane domain, and intracellular signaling domain, to improve safety and efficacy. Additionally, strategies to reduce on-target, off-tumor toxicities, such as affinity tuning, logic-gated CARs, and suicide gene systems, are discussed. The review emphasizes the need for further research to expand the clinical benefits of CAR T cell therapy to a broader range of malignancies.The article discusses the current challenges and strategies to overcome limitations in CAR T cell therapy, particularly in the context of solid tumors and other cancers. Key challenges include severe toxicities, poor tumor infiltration, suboptimal persistence, antigen escape, and manufacturing issues. To address these, researchers are developing innovative CAR designs, such as using MHC-dependent TCR-mimic CARs, targeting intracellular tumor-associated antigens, and incorporating cytokines or other ligands to enhance T cell activation. The article also highlights the importance of optimizing the CAR structure, including the antigen-binding domain, hinge, transmembrane domain, and intracellular signaling domain, to improve safety and efficacy. Additionally, strategies to reduce on-target, off-tumor toxicities, such as affinity tuning, logic-gated CARs, and suicide gene systems, are discussed. The review emphasizes the need for further research to expand the clinical benefits of CAR T cell therapy to a broader range of malignancies.