Recent advances in bispecific natural killer cell engagers for cancer immunotherapy.

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes capable of eliminating malignant cells independently of major histocompatibility complex (MHC) - restricted antigen recognition. This makes them particularly valuable in tumors that evade adaptive immune surveillance through MHC antigen loss or impaired processing. However, tumor-intrinsic immune evasion mechanisms and suppressive tumor microenvironments frequently impair endogenous NK cell activity, limiting the effectiveness of nontargeted autologous NK cell-based approaches.Bispecific and multispecific NK cell engagers (NKCEs) have emerged as promising immunotherapeutics designed to redirect NK cells toward tumor-associated antigens while delivering potent activating signals. These engineered molecules typically engage activating NK receptors (e.g. CD16a, NKG2D, or NKp46) to promote immune synapse formation and antigen-specific cytotoxicity. Advances in molecular engineering have enabled the development of multispecific platforms that integrate dual tumor antigen targeting, multireceptor activation, and cytokine support - particularly interleukin-15-, to enhance NK cell persistence, expansion, and functional durability.This review highlights progress in NKCE design, preclinical efficacy, and early clinical translation, while addressing safety considerations, mechanisms of resistance, and rational combination strategies, such as with adoptive NK cell therapies and checkpoint inhibitors. Collectively, NKCEs represent versatile, drug-like immunotherapies with the potential to overcome key limitations of monoclonal antibody and T cell - based therapies.