The immunotherapy landscape in AML: Defining knowledge gaps toward rational combinatorial strategies

Immunotherapy has dramatically improved outcomes in lymphoid malignancies. In B cell cancers, CD19-directed CAR T cells and T-cell engagers have produced high remission rates and durable responses, now forming the cornerstone of treatment in many relapsed or refractory settings. In contrast, acute myeloid leukemia (AML) has not experienced a comparable breakthrough. To date, only antibody-drug conjugates have reached regulatory approval, with gemtuzumab ozogamicin approved in combination with intensive induction and consolidation therapy for newly diagnosed CD33-positive AML. This divergence is rooted in the biological and immunologic complexity of AML. Unlike B-cell malignancies with lineage-restricted surface markers such as CD19, AML lacks leukemia-specific antigens. Most targets are shared with normal hematopoietic progenitors, leading to on-target/off-leukemia toxicity. Moreover, AML exerts local and systemic immunosuppression through both tumor-intrinsic and microenvironmental mechanisms, limiting T-cell persistence and function. This review will introduce the current immunotherapy platforms under investigation in AML, starting with antibody-based approaches, followed by T-cell redirecting therapies, and culminating in an overview of immune resistance, the bone marrow microenvironment, and strategies toward personalized combinatorial immunotherapy. By synthesizing recent clinical data and mechanistic insights, including those from early CAR and T-cell engager trials, we aim to provide a translational framework for how immunotherapy might still reshape AML care-through integration of immune contexture of the bone marrow environment aiming for rational combinatorial approaches.