Antigen-experienced NK-T cells: integrating new insights and exploring therapeutic potential in cancer immunotherapy

Conventional CD8+ T cells can acquire natural killer (NK) cell receptors upon persistent antigen exposure, forming antigen-experienced NK-T (AENK-T) cells. Their dual-state plasticity within the tumor immune microenvironment determines cancer immunotherapy outcomes. This narrative review synthesizes recent transcriptomic, epigenomic, and functional data to define the trajectory, regulation, and therapeutic relevance of AENK-T cells. The analysis establishes a "temporal hierarchy" differentiating AENK-T cells from innate-like T cells: activating NK receptors (NKG2C, NKG2D) emerge early, while inhibitory receptors (NKG2A, killer-cell immunoglobulin-like receptors, KLRB1) accumulate under sustained stimulation. Mechanistically, BCL11B downregulation and the T-bet-Zeb2 axis stabilize a cytotoxic Effector AENK-T state. Conversely, the TOX-LAG-3 loop and SOX4-ID3 axis drive transition into a suppressive Exhausted AENK-T state, mirroring terminal exhaustion. The tumor immune microenvironment accelerates this shift via hypoxia, metabolic competition, and TGF-β, contrasting with chronic infection models. Translating these findings, an evaluation of emerging strategies, such as NKG2A blockade, biomarker-guided patient selection, and next-generation chimeric antigen receptor (CAR)-T cell engineering, suggests that temporally informed approaches targeting the AENK-T trajectory may overcome current immune checkpoint therapy limitations.