The NCG-M mouse is a next-generation immunodeficient model based on the NCG strain, engineered to enhance human immune system reconstruction. To improve the engraftment and function of human hematopoietic cells, three human cytokine genes—SCF (KITLG), GM-CSF (CSF2), and IL-3—were knocked into the genome. These cytokines support the development and expansion of myeloid cells, including dendritic cells, monocytes, and macrophages, as well as promote the maturation of T cells, B cells, and NK cells. Compared to standard NCG mice, NCG-M shows improved myeloid lineage support and enhanced human immune cell functionality, making it a powerful tool for studies in acute myeloid leukemia (AML), immuno-oncology, and human immune system reconstitution. This model can also be used in combination with other human cytokine knock-in strains for tailored immune research applications.