Ziyan Kong, Jinke Wang
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable clinical efficacy across a spectrum of hematological malignancies, with particularly profound responses observed in B-cell leukemias, lymphomas, and multiple myeloma. However, the clinical benefits of CAR-T cell therapy have not yet been effectively extended to most solid tumors. This limitation arises from multiple biological and structural barriers, including the paucity of truly tumor-specific antigens, variable antigen expression and loss, inefficient trafficking and infiltration, and the presence of a highly immunosuppressive tumor microenvironment (TME). These obstacles not only restrict tumor recognition and intratumoral accumulation but also impair CAR-T-cell persistence, cytotoxicity, and durable tumor control, while promoting immune escape and increasing the likelihood of on-target, off-tumor toxicity. To address these challenges, diverse engineering strategies are being developed to improve the safety, efficacy, and adaptability of CAR-T cell therapy in solid tumors. These include Boolean logic-gated receptors, multi-antigen and retargeting platforms, locoregional delivery and trafficking-enhancing approaches, checkpoint blockade, armored CAR-T cells, synthetic receptors that rewire inhibitory signals, and emerging in vivo engineering approaches. In this review, we discuss how these next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.