Natural killer cell engagers: From bi‐specific to tri‐specific and tetra‐specific engagers for enhanced cancer immunotherapy

Abstract Natural killer cell engagers (NKCEs) are a specialised subset of antibodies capable of simultaneously targeting endogenous NK cells and tumour cells, generating precise and effective cytolytic responses against cancer. This review systematically explores NK engagers as a rising star in NK‐mediated immunotherapy, specifically focusing on multi‐specific engagers. It examines the diverse configuration of NKCEs and how certain biologics could be employed to boost NK activity, including activating receptor engagement and cytokine incorporation. Some challenges and future perspectives of current NKCEs therapy are also discussed, including optimising pharmacokinetics, addressing the immunosuppressive tumour microenvironment and exploring potential combinatorial approaches. By offering an in‐depth analysis of the current landscape and future trajectories of multi‐specific NKCEs in cancer treatment, this review serves as a valuable resource for understanding this promising field of immunotherapy. Highlights Innovative NKCEs : NK cell engagers (NKCEs) represent a promising new class of immunotherapeutics targeting tumours by activating NK cells. Multi‐specific formats : The transition from bi‐specific to multi‐specific NKCEs enhances their versatility and therapeutic efficacy. Mechanisms of action : NKCEs have the potential to improve NK cell activation by engaging activating receptors and incorporating cytokines. Clinical potential : Current clinical trials demonstrate the safety and efficacy of various NKCEs across different cancer types. Future research directions : Optimising NKCE designs and exploring combination therapies are essential for overcoming challenges in cancer treatment.