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Background Natural killer (NK) cells represent a crucial component of innate immunity with inherent ability to recognize and eliminate malignant cells. The development of NK cell-based immunotherapies has gained significant momentum in recent years, particularly for treating hematological malignancies. To enhance the functional aspects of NK cells and to achieve stronger, sustained anti-tumor responses, combination strategies are investigated. They are focused on optimizing NK cell potency, persistence and tumor targeting using monoclonal antibodies, multi-specific NK cell engagers and immune modulators like cytokines.Methods This study evaluated an innovative off-the-shelf allogeneic NK cell therapy generated using Sanofi’s proprietary platform, which employs plasma membrane particles from K562 cells expressing membrane-bound IL-21 and 4-1BB ligand for cell expansion. To optimize therapeutic outcomes, we tested various combination strategies in preclinical mouse models using immunodeficient NOG mice, transgenic or not for human IL-15. All studies were done in an accredited facility with all compliance to local, state and international guidelines and requirements.Results We demonstrated that human IL-15 is required for the engraftment and long-term maintenance of functional huNK cells in mouse. The study also explored the potential of pegenzileukin, a PEGylated non-alpha rhIL-2 variant engineered for preferential binding to IL-2 βγ receptors. This combination of NK cell adoptive transfer with pegenzileukin treatment resulted in remarkable enhancement of NK cell persistence, with up to 28-fold increase in NK cell numbers and improved tissue infiltration in both lung and liver. In a disseminated lymphoma model, the combination of NK cells with anti-CD20 monoclonal antibody (mAb) demonstrated superior efficacy, achieving an increased lifespan (ILS) as compared to anti-CD20 mAb monotherapy. NK cells remained detectable in peripheral blood for at least four weeks post-transfer.We also developed multiple myeloma models for the investigation of a novel approach using CD38 knockout NK cells in combination with anti-CD38 mAb therapy. Using FcγR-knockout immunodeficient mice to minimize interference from murine immune cells, we demonstrated that CD38KO NK cells effectively resisted anti-CD38 mAb-mediated fratricide killing, while wild-type NK cells showed significant depletion. This genetic modification enabled sustained therapeutic NK cell persistence in the presence of anti-CD38 mAb treatment.Conclusions These comprehensive findings demonstrate the enhanced therapeutic potential of strategically designed NK cell combination approaches. The study provides compelling evidence for improved antitumor activity and NK cell persistence when combined with monoclonal antibodies and cytokine therapy. These results establish a strong foundation for further clinical development of NK cell-based combination immunotherapies in oncology.