CAR-iNKT cells for cancer therapy: a comprehensive review of engineering, mechanisms, and clinical progress.

Abstract

Chimeric antigen receptor (CAR)-modified T cells, as a revolutionary cancer immunotherapy, have achieved remarkable success in hematologic malignancies. However, the therapy is hindered by severe toxicity, complex manufacturing, and suboptimal efficacy in solid tumors. Invariant natural killer T (iNKT) cells combine features of T cells and NK cells, bridging innate and adaptive immunity. Beyond direct cytotoxic functions, iNKT cells exert indirect antitumor effects through interactions with other immune cells while also modulating the tumor microenvironment (TME). Their exceptional TME infiltration capacity offers hope for solid tumor treatment. Leveraging their inherent major histocompatibility complex (MHC)-independent cytotoxicity, iNKT cells offer a viable strategy for developing "off-the-shelf" CAR cell products. Consequently, CAR-iNKT cell therapies developed by introducing CAR technology into iNKT cells demonstrate extraordinary potential as a next generation tumor immunotherapy. Despite being established and garnering attention, CAR-iNKT cell therapy remains nascent with numerous obstacles. This review comprehensively discusses CAR-iNKT cell therapy, from the fundamental biology of iNKT cells to the latest advances in engineering and clinical translation, offering new perspectives for its research, development, and application. A comprehensive literature search was conducted using [PubMed, Embase, and Web of Science] for articles published between [January 1900 and March 2026].