A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T‐Cell Acute Lymphoblastic Leukemia

Compromised immunosurveillance leads to chemotherapy resistance anddisease relapse of hematological malignancies. Amino acid metabolismregulates immune responses and cancer; however, a druggable amino acidmetabolite to enhance antitumor immunosurveillance and improve leukemiatargeting-therapy efficacy remains unexplored. Here, an L-phenylalaninepolymer, Metabolic Reprogramming Immunosurveillance ActivationNanomedicine (MRIAN), is invented to effectively target bone marrow (BM)and activate the immune surveillance in T-cell acute lymphoblastic leukemia(T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALLmurine model. Stable-isotope tracer and in vivo drug distribution experimentsshow that T-ALL cells and MDSCs have enhanced cellular uptake ofL-phenylalanine and MRIANs than normal hematopoietic cells andprogenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox)specifically targets T-ALL cells and MDSCs but spare normal hematopoieticcells and hematopoietic stem and progenitor cells with enhanced leukemicelimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicityand myeloablation side effects in treating T-ALL mice. Mechanistically,MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity andreduces ROS levels in MDSCs to disturb their immunosuppressive functionand increase their differentiation toward normal myeloid cells. Overall, a novelamino acid metabolite nanomedicine is invented to treat T-ALL through thecombination of leukemic cell targeting and immunosurveillance stimulation.