The AML immune paradox: decoding escape pathways and pioneering checkpoint, vaccine, and combination strategies.

Acute myeloid leukemia (AML) remains a high-mortality cancer due to its aggressive nature and immunosuppressive tumor microenvironment (TME), which enables evasion of immune surveillance. Despite chemotherapy and targeted therapies, 5-year survival is ~ 30%, necessitating novel immunotherapies. AML suppresses cytotoxic T/NK cells by co-opting regulatory pathways, creating an "immune paradox." Emerging strategies aim to disrupt this evasion. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 nivolumab and anti-CD47 magrolimab, combined with hypomethylating agents (HMAs), enhance T-cell activity and phagocytosis, especially in TP53-mutated AML. Therapeutic vaccines targeting leukemia-associated antigens (e.g., WT1, PRAME) via dendritic cell fusion show early success in prolonging remission. Combinatorial approaches, like HMAs with STING agonists or dual checkpoint blockade, target multiple immunosuppressive pathways to overcome resistance. Challenges include TME heterogeneity, therapy-resistant leukemia stem cells, toxicities (e.g., anemia, cytokine release syndrome), relapse from clonal evolution, and a lack of predictive biomarkers. Autologous therapies face economic and logistical hurdles, driving demand for scalable solutions. Advances in single-cell genomics, AI, and synthetic biology are identifying novel targets (TIM-3, TIGIT, VISTA) and improving patient stratification. Integrating these innovations may transform AML into a chronic condition, bridging preclinical potential to clinical impact. In this review, we aim to evaluate mechanisms, challenges, and future directions of immunotherapies in AML with highlighting ICIs and vaccination to improve therapeutic outcomes.