Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, particularly for B-cell leukemias and lymphomas. However, challenges such as severe toxicities, limited efficacy in solid tumors, antigen escape, restricted trafficking, and tumor infiltration persist. The host and tumor microenvironment also significantly impact CAR-T cell function. To overcome these limitations, innovative strategies are being developed to engineer more powerful CAR-T cells with improved anti-tumor activity and reduced toxicity. This review discusses recent advancements in CAR-T cell engineering, including dual and tandem CAR constructs, targeting tumor-restricted post-translational modifications, and enhancing CAR-T cell trafficking and tumor infiltration. Additionally, strategies to address the immunosuppressive microenvironment and reduce CAR-T cell-associated toxicities, such as "off-switches" and immunogenicity reduction, are explored. These efforts aim to improve the clinical efficacy and safety of CAR-T cell therapy for both hematological malignancies and solid tumors.Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, particularly for B-cell leukemias and lymphomas. However, challenges such as severe toxicities, limited efficacy in solid tumors, antigen escape, restricted trafficking, and tumor infiltration persist. The host and tumor microenvironment also significantly impact CAR-T cell function. To overcome these limitations, innovative strategies are being developed to engineer more powerful CAR-T cells with improved anti-tumor activity and reduced toxicity. This review discusses recent advancements in CAR-T cell engineering, including dual and tandem CAR constructs, targeting tumor-restricted post-translational modifications, and enhancing CAR-T cell trafficking and tumor infiltration. Additionally, strategies to address the immunosuppressive microenvironment and reduce CAR-T cell-associated toxicities, such as "off-switches" and immunogenicity reduction, are explored. These efforts aim to improve the clinical efficacy and safety of CAR-T cell therapy for both hematological malignancies and solid tumors.