The clinical landscape of CAR-engineered unconventional T cells

Unconventional T cells, such as invariant natural killer T (iNKT), γδ T, and mucosal-associated invariant T (MAIT) cells, play a pivotal role in bridging innate and adaptive immunity. Their capacity for rapid tumor targeting and effective modulation of the tumor microenvironment (TME) makes them promising candidates for cancer immunotherapy. Advances in chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly for treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing their viability as off-the-shelf therapeutic options. We provide a comprehensive analysis of the clinical applications of CAR-engineered unconventional T cells, focusing on genetic modifications, manufacturing processes, preconditioning regimens, and dosing strategies. We discuss successful examples from recent clinical trials and explore future directions for utilizing these cells in cancer therapy and beyond.