Cancer immunotherapy that takes advantage of the immune system to eliminate tumor cells has become an indispensable weapon for cancer treatment in the last decades. Despite the tremendous recent progress in this field, cancer treatment has not reached that desirable goal of frequently becoming a chronic disease. Unfortunately, tumor heterogeneity and tumor immune escape mechanisms as well as intrinsic immune regulatory mechanisms account for the many reasons that cancer relapse still occurs. NK-cell immunobiology and the regulation of its activation has proven far more complex than was initially thought through the existence of self-regulatory mechanisms that influence NK cell activation or function leading to an exhaustion phenotype. Additionally, NK cell-based immunotherapy has also proven to have important limitations and fail to accomplish long-term efficacy due to NK cell specific tumor evasion mechanisms such as recruitment of immunosuppressor cells, downregulation of activating receptors, and/or extrinsic induction of exhaustion, among other mechanisms. Therefore careful analysis of the pathways involved in NK cell activation that might limit NK cell function are critical to understand how NK cells are regulated and to be able to exploit this immune cell as an immunotherapeutic weapon. Here, we are exploring different approaches to induce a stronger and sustained NK cell activation and function to uncover a novel intrinsic and complex regulatory mechanism that controls cytotoxicity against tumors and limits NK cell-based immunotherapy efficacy. This analysis is helping us to develop a new, and needed strategy to expand ex vivo activated NK cells and improve overall NK cell function utilizing cutting edge technology such as available new mAbs, siRNA, synthetic drugs and/or selection by immunomagnetic or FACS cell sorting, that makes possible to engineer NK cells to reach our expectations. Thus far, forcing the production of IL-15 has given promising results, and has proven efficacious in expanding and activating NK cells with strong anti-tumor responses. Therapeutic efficacy will be evaluated next in clinically meaningful mouse and xenograft models with relevant mouse and human tumor models respectively to demonstrate the versatility and the clinical translation capabilities of our proposed therapeutic strategies. Therapeutic efficacy will be also evaluate in combination with current immune checkpoint blockade therapies to accomplish an even better outcome. These strategies share the goal of achieving more efficacious immunotherapy approaches, especially for the treatment of hematological and metastatic cancers, to prevent cancer relapse and limit treatment-related toxicities, prolonging tumor-free survival rate and improving quality of life of cancer patients.