Abstract
Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising types of immunotherapies for the treatment of cancer. Unlike conventional T cells, which recognize antigens only when presented by the major histocompatibility complex (MHC), CARs use an antibody-derived binding domain to recognize native tumor-associated surface antigens directly, enabling MHC-independent target recognition. The two main cytotoxic mechanisms used by CAR T cells are the quick release of lytic granules containing granzymes and perforin to cause target cell apoptosis and the activation of death-receptor pathways (FasL/Fas or TRAIL) to cause caspase-dependent cell death. Four generations of CAR designs have been created to improve therapeutic efficacy and an advanced fifth generation is under development. Although CAR-T therapies have been very successful in treating hematological malignancies, their efficacy in solid tumors is limited because of immunosuppressive tumor microenvironments, tissue architecture, and antigen expression patterns that prevent CAR-T cell infiltration, activation, and persistence. With encouraging but early results, CAR T-cell therapy is moving forward into many clinical studies aimed at different solid tumors. Antigens including epidermal growth factor receptor (EGFR), mesothelin (MSLN), Disialoganglioside 2 (GD2), and B7-H3 were the subject of important clinical research conducted between 2021 and 2025. Emerging cellular treatments such as Chimeric Antigen Receptor Natural Killer cells (CAR-NK), CAR-macrophages and T-cell receptor (TCR)-engineered T cells offer alternate options to circumvent the limitations of CAR T-cells in solid tumors. This review aims to examine the evolution of next-generation CAR-T cell therapy for solid tumors by highlighting recent innovations, key clinical advancements, and persisting therapeutic challenges. It further seeks to analyze the biological and translational barriers limiting efficacy in solid malignancies and to explore emerging strategies and future directions that may enhance clinical outcomes.