The discovery of NK cells in 1975 unveiled a lymphocyte population capable of lysing malignant cells without prior sensitization - a phenomenon that defied then-dominant paradigms of antigen-specific immunity [1], [2]. This seminal observation laid the foundation for what would become a cornerstone concept in immunology: Kärre’s "missing-self" hypothesis [3], [4], which established NK cells as sentinels detecting the absence of self-MHC class I molecules, a hallmark of cellular transformation. Subsequent decades revealed the sophisticated receptor-ligand systems (e.g., KIR–MHC-I, NKG2D–stress ligands) that govern NK cell target discrimination [5], [6]. The 2000s witnessed conceptual breakthroughs with the identification of NK cell memory-like responses, challenging the strict dichotomy between innate and adaptive immunity [7], [8], and the characterization of MHC-I-dependent "licensing" as a prerequisite for full functional competence [9], [10]. Advancements in the 2010s, particularly single-cell transcriptomics and CRISPR-Cas9-mediated genomic editing, systematically decoded NK cell heterogeneity and enabled precise therapeutic engineering [11]. Clinically, NK cell-based immunotherapy has progressed from cytokine augmentation (e.g., IL-2, IL-15) to molecularly engineered strategies, including: FDA-approved IL-15 superagonists (e.g., ALT-803) enhancing NK cell activation and persistence; Bispecific/trispecific killer cell engagers (BiKEs/TriKEs) targeting tumor-associated antigens; Adoptive transfer of ex vivo-expanded allogeneic NK cells; Chimeric antigen receptor (CAR)-NK constructs with enhanced specificity. Notably, NK cells exhibit a favorable toxicity profile, with minimal induction of graft-versus-host disease (GVHD) or cytokine release syndrome (CRS) compared to CAR-T therapies, underscoring their potential as off-the-shelf therapeutics [12], [13].

Despite these advances, critical challenges persist [14]. The metabolic constraints of adoptively transferred NK cells in nutrient-deprived TMEs remain poorly understood, and the functional consequences of receptor crosstalk (e.g., between inhibitory KIRs and activating NCRs) demand further elucidation. Moreover, emerging evidence suggests that NK cell dysfunction in solid tumours follows distinct trajectories from that observed in haematological malignancies, necessitating disease-specific therapeutic design. As the field moves beyond proof-of-concept studies, the next decade will require mechanistic rigour with deconvolution of NK cell–other cell interactions at single-cell and spatial resolution; translational innovation with the development of in vivo NK cell expansion protocols and engineered cytokine depots; and clinical boldness with rational combinations with immune checkpoint blockade, BiKEs/TriKEs, cytokines and small molecules. By integrating fundamental insights with cutting-edge engineering, NK cell therapies are poised to transition from supportive players to central modalities in cancer immunotherapy.