◥Despite strong biological rationale for the use of type-I IFNs for the treatment of acute myeloid leukemia (AML), their usage is limited to few hematologic malignancies. Here, we propose that innate immune sensing machinery, particularly the stimulator of IFN genes pathway, may be exploited to deliver antileukemic effects in AML. Has Acute Myeloid Leukemia Treatment Stagnated?Acute myeloid leukemia (AML) is a malignancy of the bone marrow driven by proliferation of immature myeloid cells (1, 2). Current treatment is relatively standardized, including chemotherapy with anthracycline/cytarabine combination, for which most patients reach complete clinical response, followed by either consolidation chemotherapy or allogeneic stem cell transplantation (SCT; ref.3). Efficacy of current standard-of-care chemotherapeutics is limited, associated with serious toxicity, and has changed little in the past four decades, warranting the need for new therapies. Use of type-I IFNs for AML treatment dates back to the early 1980s, with several clinical trials using recombinant and modified formulations of type-I IFNs for patients relapsing upon hematopoietic SCT or postremission strategy to prevent recurrence (4). However, with only modest clinical outcome, firm conclusion regarding the efficacy of type-I IFN could not be made. Emerging evidence now suggests targeting innate immune sensing mechanisms that regulate type-I IFN activity in response to viral infections may be exploited and refined to deliver antileukemic effects in AML rather than systemic delivery of type-I IFN regimens.The "Traditional" Type-I IFN in AML Type-I IFNs are recognized as antiviral cytokines, induced in response to viruses. In addition to virus-infected cells, they are also secreted by T cells, macrophages, and natural killer cells, and activate lymphocytes in the immediate vicinity to develop their cytotoxic potential (5). This drives amplification of the lytic arm of the immune response, which may form the basis of their antitumoral activity. Type-I IFNs have been used to treat hematologic malignancies, such as hairy cell leukemia, chronic myeloid leukemia, and other myeloproliferative neoplasms. The FDA approved IFNa (IFNa2b) in 1986 for the treatment of hairy cell leukemia in the United States. However, type-I IFN has not been a treatment option in AML due to inconsistent patient response and toxicities ranging from fever, skin rash, somnolence, generalized seizure, and autoimmune symptoms to thyroid dysfunction and acute graftversus-host disease (GVHD; refs. 4,6). Type-I IFN signaling appears to negatively impact the development of leukemia, in line with its downstream functions, such as increase in rate of apoptosis, increase in AML immunogenicity, and decrease in cell proliferation (7). Despite this, it is unclear as to why type-I IFN treatment for AML is not as robust an envisioned.