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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. [ABSTRACT FROM AUTHOR]

Summary: The ability of cells of the immune system to acquire features such as increased longevity and enhanced secondary responses was long thought to be restricted to cells of the adaptive immune system. Natural killer (NK) cells have challenged this notion by demonstrating that they can also gain adaptive features. This has been observed in both humans and mice during infection with cytomegalovirus (CMV). The generation of adaptive NK cells requires antigen‐specific recognition of virally infected cells through stimulatory NK receptors. These receptors lack the ability to signal on their own and rather rely on adaptor molecules that contain ITAMs for driving signals. Here, we highlight our understanding of how these receptors influence the production of adaptive NK cells and propose areas in the field that merit further investigation. [ABSTRACT FROM AUTHOR]

One of the KIR allele, KIR3DL1*007, was associated with the progression to acquired immunodeficiency syndrome and not with the susceptibility to HIV‐1 infection in the Japanese and Indian populations, implying that KIR3DL1*007‐positive NK cells might eliminate HIV‐infected cells less effectively than NK cells bearing the other KIR3DL1 alleles or KIR3DS1 alleles. [ABSTRACT FROM AUTHOR]

X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48+ or CD48− KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48+ EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48− targets, such as mature DCs. Self-iNKR− NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients' immune defect. [ABSTRACT FROM AUTHOR]

Citation Laskarin G, Redzovic A, Vukelic P, Veljkovic D, Gulic T, Haller H, Rukavina D. Phenotype of NK cells and cytotoxic/apoptotic mediators expression in ectopic pregnancy. Am J Reprod Immunol 2010 Problem The expression of cytotoxic/apoptotic mediators and the phenotype characteristics of uterine NK cells (uNK) in tubal ectopic pregnancy (EP) were investigated. Method of study Samples of uterine decidua and tubal mucosa as well as peripheral blood (PB) of the same women with EP were used for phenotype characterization of NK cells and detection of cytotoxic/apoptotic mediators and IL-15. Results In tubal mucosa, perforin, FasL, granulysin and IL-15 were almost completely absent, but they were present in normal and EP uterine deciduas. TRAIL was present on trophoblast and tubal mucosa, contrary to its lack in normal and EP uterine decidua. CD16−CD56dim NK cells, mostly CD94− and NKG2A−, predominate in tubal mucosa, whereas CD16−CD56bright NK cells, predominantly CD94+ and NKG2A+ prevail in EP uterine decidua. NK cells at the EP implantation site express lower percentages of perforin and granulysin, but they express a higher percentage of TRAIL than do EP uterine decidual and PB NK cells. Lower percentage of TNF-α-expressing and IL-4-expressing NK cells were found at the implantation site compared to EP uterine decidua. Conclusions Authentic uNK cell population seems to be insufficient to restrict trophoblast invasion because of low expression of cytotoxic/apoptotic mediators. [ABSTRACT FROM AUTHOR]

KIR2DS2*00104 lacks a distinctive synonymous substitution of KIR2DS2 in nucleotide 418 that affects KIR genotyping. [ABSTRACT FROM AUTHOR]