Novel therapy in higher-risk myelodysplastic neoplasms (HR-MDS). (A) Targeted therapy in patients with RARα overexpressing cells with tamibarotene (SY-1425), a selective RARa agonist and blockade of the anti-apoptotic protein BCL-2 via the BH3 mimetic venetoclax; ultimately leading to apoptosis induction with the combination of hypomethylating agents. (B) Novel immune myeloid therapy targeting both the underlying leukemic stem cell (LSC)/blast as well as activating both innate and adaptive immunity. Magrolimab, and other inhibitors of the CD47/SIRPα axis, allowing for activation of antibody dependent cellular phagocytosis (ADCP) and likely subsequent adaptive immune activation via increased antigen presentation. Sabatolimab blocks the galectin-9/TIM-3 pathway leading to direct targeting of the LSC as well as T-cell activation and potentially augmentation of ADCP.