NK-Cell Engagers in Cancer Immunotherapy: Recent Advances, Translational Challenges, and Future Strategies

Natural killer (NK)-cell engagers (NKCEs) are antibody-based therapeutics that link activating receptors on NK cells to tumor-associated antigens, enabling targeted cytotoxicity. NKCE development has progressed from bispecific CD16A-directed constructs to multispecific platforms incorporating complementary activating receptors, cytokine support, and half-life engineering. These designs offer coordinated control of tumor recognition and NK-cell activation within an off-the-shelf therapeutic format with adjustable dosing and exposure. Early clinical studies demonstrate meaningful antitumor activity and an encouraging safety profile in selected hematologic malignancies, particularly when engagers are combined with preactivated, expanded allogeneic NK cells. Nevertheless, response durability remains variable, and clinical development has been complicated by biological limitations and sponsor-related discontinuations. Solid tumors present additional challenges, including antigen heterogeneity, inadequate NK-cell infiltration, stromal exclusion, and microenvironmental suppression. Soluble NKG2D ligands, particularly sMICA and sMICB, can further impair effector function, supporting investigation of combinations that restore NK-cell competence alongside engager-mediated redirection. This review examines NKCE architectures, mechanisms, clinical progress, and translational challenges. Priorities include matching engager design to tumor and effector biology, optimizing pharmacokinetic and pharmacodynamic properties, defining predictive biomarkers, and developing rational combinations that translate early responses into durable disease control.