Invariant Natural Killer T Cells in Cancer Immunotherapy: Lipid-Based Modulation, Nanotechnology, and Translational...

Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby activating dendritic cells, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs) to promote antitumor immunity. Despite their therapeutic promise, clinical translation has been limited by rapid α-GalCer clearance, induction of iNKT cell anergy following repeated stimulation, and the immunosuppressive tumor microenvironment (TME). Recent advances in lipid-engineered nanoparticle systems offer solutions to these challenges by improving ligand stability, enhancing antigen-presenting cell targeting, and enabling controlled release that sustains Th1-biased activation while reducing anergy. Liposomal and polymer-based nano-formulations enhance bioavailability and promote more durable IFN-γ-mediated responses. In parallel, chimeric antigen receptor (CAR)-engineered iNKT cells provide antigen-specific tumor targeting while preserving intrinsic CD1d-restricted immunomodulatory functions, demonstrating encouraging safety and efficacy in early-phase studies. Combination strategies further strengthen iNKT-based immunotherapy. Integration with chemotherapy, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, and cytokine support enhances effector activation, counteracts TME-induced suppression, and improves therapeutic outcomes. However, challenges remain, including optimization of dosing, control of off-target immune activation, scalable manufacturing, and long-term safety evaluation. Collectively, the convergence of nanotechnology, CAR engineering, and rational combination approaches establishes iNKT cell-based therapy as a promising next-generation immunotherapeutic strategy. Continued refinement of delivery systems, genetic engineering platforms, and translational protocols may enable durable immune reprogramming and improved clinical outcomes in resistant and immunosuppressive cancers.