The article discusses the role of the innate immune system in pediatric and adult acute myeloid leukemia (AML) and highlights the potential of targeting innate immune cells to improve immunotherapy outcomes. AML is a heterogeneous hematological malignancy characterized by uncontrolled proliferation of myeloid progenitor cells. Despite advances in traditional therapies like allogeneic hematopoietic stem cell transplantation (allo-HSCT), AML remains challenging due to treatment-related toxicity and relapse. Immunotherapies, particularly T cell-based approaches, have shown promise in other cancers but have been limited in AML. The immunosuppressive tumor microenvironment (TME) in AML is largely driven by innate immune cells, including macrophages, myeloid-derived suppressor cells (MDSCs), and natural killer (NK) cells. These cells contribute to immune evasion and therapy resistance. Macrophages in AML can be polarized toward a pro-tumorigenic M2-like phenotype, which supports leukemogenesis and therapy resistance. Tumor-associated macrophages (TAMs) are associated with poor prognosis and can suppress T cell responses. MDSCs also contribute to immunosuppression by inhibiting T cell proliferation and recruiting regulatory T cells (Tregs). NK cells are functionally impaired in AML, with reduced cytotoxic activity and increased expression of inhibitory receptors. Dendritic cells (DCs) are also involved in immune evasion, with a decrease in conventional DCs and an increase in plasmacytoid DCs in AML. Neutrophils in AML are associated with poor prognosis and can promote tumor growth and metastasis. Mast cells are involved in both innate and adaptive immune responses and may contribute to immunosuppression in AML. Targeting innate immune cells in AML is a promising strategy to overcome the immunosuppressive TME and enhance the effectiveness of immunotherapies. Strategies include repolarizing macrophages toward an anti-tumor phenotype, inhibiting MDSCs, and targeting NK cell inhibitory receptors. Several approaches, such as targeting the CD47/SIRPα axis, are currently in clinical trials for adult AML. NK cell-based immunotherapies, including adoptive NK cell transfer and CAR-NK cells, are also being explored. While these strategies show promise, challenges remain, including the need for more effective targeting of immunosuppressive cells and the development of therapies that can be applied to pediatric AML. Overall, understanding the role of the innate immune system in AML is crucial for developing more effective immunotherapies.The article discusses the role of the innate immune system in pediatric and adult acute myeloid leukemia (AML) and highlights the potential of targeting innate immune cells to improve immunotherapy outcomes. AML is a heterogeneous hematological malignancy characterized by uncontrolled proliferation of myeloid progenitor cells. Despite advances in traditional therapies like allogeneic hematopoietic stem cell transplantation (allo-HSCT), AML remains challenging due to treatment-related toxicity and relapse. Immunotherapies, particularly T cell-based approaches, have shown promise in other cancers but have been limited in AML. The immunosuppressive tumor microenvironment (TME) in AML is largely driven by innate immune cells, including macrophages, myeloid-derived suppressor cells (MDSCs), and natural killer (NK) cells. These cells contribute to immune evasion and therapy resistance. Macrophages in AML can be polarized toward a pro-tumorigenic M2-like phenotype, which supports leukemogenesis and therapy resistance. Tumor-associated macrophages (TAMs) are associated with poor prognosis and can suppress T cell responses. MDSCs also contribute to immunosuppression by inhibiting T cell proliferation and recruiting regulatory T cells (Tregs). NK cells are functionally impaired in AML, with reduced cytotoxic activity and increased expression of inhibitory receptors. Dendritic cells (DCs) are also involved in immune evasion, with a decrease in conventional DCs and an increase in plasmacytoid DCs in AML. Neutrophils in AML are associated with poor prognosis and can promote tumor growth and metastasis. Mast cells are involved in both innate and adaptive immune responses and may contribute to immunosuppression in AML. Targeting innate immune cells in AML is a promising strategy to overcome the immunosuppressive TME and enhance the effectiveness of immunotherapies. Strategies include repolarizing macrophages toward an anti-tumor phenotype, inhibiting MDSCs, and targeting NK cell inhibitory receptors. Several approaches, such as targeting the CD47/SIRPα axis, are currently in clinical trials for adult AML. NK cell-based immunotherapies, including adoptive NK cell transfer and CAR-NK cells, are also being explored. While these strategies show promise, challenges remain, including the need for more effective targeting of immunosuppressive cells and the development of therapies that can be applied to pediatric AML. Overall, understanding the role of the innate immune system in AML is crucial for developing more effective immunotherapies.