Advancements and Challenges of Gamma Delta <b>(γδ)</b> T Cell- and Invariant Natural Killer T (iNKT) Cell-Based Cancer Immunotherapies

Gamma delta (γδ) T cells and invariant natural killer T (iNKT) cells are unconventional T cells with limited T cell receptor (TCR) diversity. Both can recognize lipid or non-peptide antigens, often through cluster of differentiation 1d (CD1d), rapidly produce cytokines, express natural killer (NK) cell markers, and are mainly found in mucosal and barrier tissues. Acting as a bridge between innate and adaptive immunity, they show great promise for cancer immunotherapy. Developing γδ T and iNKT cells for treatment involves shared features like thymic origin, MHC-independent recognition, rapid cytotoxicity, low graft-vs.-host disease (GvHD) risk, ex vivo expansion, and genetic modification, making them suitable for adoptive cell therapies. While their mechanisms are similar, iNKT cells rely on CD1d-mediated antigen presentation, provided by CD1d-expressing antigen-presenting cells (APCs) or engineered cell lines, to activate their invariant TCR and expand effectively. Chimeric antigen receptors (CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits. Early clinical trials have shown encouraging results, and their completion will confirm their potential for future treatments. This review explores the biology and mechanisms of γδ T and iNKT cells, focusing on how APCs, cytokines, feeder cells, and CARs contribute to boosting their cytotoxic function, cytokine production, and expansion, enhancing their promise as cancer immunotherapies. It also explores the advancements and challenges in developing γδ T and iNKT cell-based immunotherapies, with preclinical and early clinical outcomes offering promising insights.