Targeting GLP-1R and IL-17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation-driven model.

Obesity is increasingly implicated in hematopoietic malignancies, yet its role in mutation-driven myeloid leukemias remains unclear. Using UK Biobank data from over 440,000 individuals, we found obesity traits including elevated BMI and waist-to-hip ratio were associated with type 2 diabetes, increased plasma IL-17A levels, reduced glucagon-like peptide 1 receptor (GLP-1R) expression, and heightened risk of myeloid malignancies. Transplantation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11) (Shp2E76K/+) mutant hematopoietic stem/progenitor cells into obese mice demonstrated that metabolic inflammation accelerated leukemogenesis via myeloid cell expansion, lipid metabolic rewiring, IL-17A activation, and accumulation of M2-like tumor-associated macrophages (TAMs), accompanied by T cell exhaustion and impaired antigen presentation. Notably, dual therapy with an anti-IL-17A antibody and a GLP-1R agonist reversed these effects by reducing M2-like TAMs, restoring Ciita-dependent antigen presentation and Tyk2-mediated IFN-γ signaling, reactivating T cell responses, and reducing leukemic burden. These findings establish IL-17A-driven, metabolism-coupled immunosuppression as a mechanistic link between obesity and protein tyrosine phosphatase 2-mutant (SHP2-mutant) myeloid leukemias, highlighting a tractable therapeutic strategy for patients with obesity at high risk for other diseases and their complications.