Application of CAR-T therapy in solid tumors: current opportunities and challenges.

In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has achieved substantial progress in treating hematologic malignancies. However, its efficacy in solid tumors remains limited due to various biological and logistical challenges. This review systematically summarizes the advancements in CAR-T therapy for solid tumors, including lung cancer, pancreatic cancer, neuroblastoma, and breast cancer. It traces the progression of CAR-T cell design from the first to the fifth generation and explores the roles of key functional modules, such as scFv, hinge regions, and costimulatory domains. Major barriers to CAR-T application in solid tumors are discussed, including antigen heterogeneity, the lack of specific targets, CAR-T cell exhaustion, the immunosuppressive tumor microenvironment (TME), and physical barriers within tumor tissues. Additionally, the review highlights emerging strategies and recent developments from 2023 to 2025, such as bispecific and multispecific CAR-T cells, regional administration techniques, logic-gated CAR constructs, safety switches, and novel approaches to modulating the TME. Despite considerable challenges, the integration of these cutting-edge technologies is advancing CAR-T therapy for solid tumors, providing new prospects for patients with refractory solid malignancies. Finally, future directions for CAR-T applications in solid tumors are discussed.