CAR-T cell therapy for solid tumors: antigen landscape, biological barriers, and engineering strategies for clinical translation

Chimeric Antigen Receptor T (CAR-T) cell therapy has emerged as a promising therapeutic option, particularly for refractory and relapsed leukemias. However, its efficacy in treating solid tumors, including lung, ovarian, gastric, and breast cancers, remains limited by several challenges. Recent studies have highlighted CAR-T cell immunotherapy as a potential treatment for these malignancies, utilizing genetically engineered T cells that target specific tumor antigens. For successful therapy, it is crucial to identify antigens that are selectively expressed on tumor cells but not on normal tissues. In lung cancer, however, the lack of specific tumor-associated antigens, the immunosuppressive tumor microenvironment, limited CAR-T cell infiltration, and off-target effects complicate the development of effective CAR-T therapies. This review outlines the fundamental structure and generation of CAR-T cells, summarizes key tumor-associated antigens targeted in clinical trials for these cancers, and discusses the current challenges and emerging strategies. The goal is to provide insights and potential approaches to enhance the design and execution of preclinical and clinical CAR-T cell therapies for these solid tumors.