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Leptin-Induced IDO1 Regulates the Balance of Suppressive and Stimulatory Functions in Tumor-associated Myeloid Cells

ABSTRACT: Obesity increases the incidence and aggressiveness of multiple cancer types but is paradoxically associated with improved response to immunotherapy. The underlying mechanisms are poorly understood. Here, we show that intratumoral levels of leptin, a factor contributing to the development of obesity, is associated with high IDO1 in tumor tissues and tumor-associated myeloid cells and with poor outcomes in cancer patients. Leptin upregulates IDO1 through STAT3 and NF-κB pathways and synergizes with IFNγ in activating the kynurenine pathway in human myeloid cells, resulting in suppression of T cell activation. However, leptin-exposed macrophages also produce multiple T cell-activating and Th1- and Th17-driving factors. This result allows IDO1 inhibitors to reprogram the function of leptin-exposed macrophages from metabolic suppression to enhanced immunostimulatory activity. Our findings indicate a novel role of leptin-induced IDO1 in regulating the balance between the obesity-associated inflammation and immune suppression, suggesting that obesity and leptin levels may predict clinical benefits of IDO1/kynurenine modulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305292 | GEO | 2026/09/30

REPOSITORIES: GEO

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