CAR-iNKT cell therapy: mechanisms, advantages, and challenges

In recent years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a groundbreaking approach in cancer immunotherapy. Particularly in hematologic malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL), B cell lymphomas and multiple myeloma. CAR-T therapy has demonstrated remarkable clinical efficacy, leading to the approval of several CAR-T cell products and offering significant benefits to numerous leukemia patients. Despite these successes, the application of CAR-T cells in solid tumors remains limited due to significant challenges, including immunosuppressive tumor microenvironments, heterogeneous antigen expression, and treatment-associated toxicities. In parallel with CAR-T development, researchers are investigating other immune cell platforms to overcome these obstacles. Among these, invariant natural killer T (iNKT) cells have garnered increasing attention for their unique immunological properties. Unlike conventional T cells, iNKT cells are a subset of T lymphocytes characterized by the expression of a semi-invariant T-cell receptor (TCR) that recognizes lipid antigens presented by CD1d molecules. This distinctive antigen recognition mechanism enables iNKT cells to bridge innate and adaptive immunity, granting them potent antitumor activity and the ability to modulate the tumor microenvironment. Additionally, iNKT cells exhibit intrinsic resistance to exhaustion and an enhanced ability to infiltrate solid tumors compared to traditional T cells. Building on these properties, researchers are leveraging CAR technology to enhance iNKT cell tumor-targeting capabilities, aiming to overcome barriers encountered in solid tumor therapy. This review provides an in-depth discussion of the application and therapeutic potential of CAR-iNKT cells in cancer immunotherapy, with a focus on their advantages over conventional CAR-T cells and their role in addressing the challenges of solid tumor treatment.