RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression
Recently an article authored by Augusto Bleve and colleagues was published on AACR Cancer Discovery.
RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression
Authors: Augusto Bleve et. al
In this article, the authors show that lipid metabolism plays a crucial role in shaping the immune landscape of cancer. They highlight the retinoic-acid-related orphan receptor gamma (RORγ) as a key sensor of lipid disorders, activated by cholesterol metabolites and driving cancer-associated emergency myelopoiesis.
Their findings reveal that both cancer and a hypercholesterolemic diet independently or synergistically promote RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), thereby supporting tumor progression. Additionally, they demonstrate that tumor-induced IL-1β and IL-6 upregulate hepatic PCSK9 expression in both preclinical models and patients.
Importantly, they show that lowering cholesterol levels through genetic or pharmacological inhibition of PCSK9 prevents MDSC expansion, reduces M2 TAM accumulation, and suppresses tumor growth in a RORγ-dependent manner, ultimately enhancing anti-tumor immunity. This study establishes RORγ as a link between hypercholesterolemia and pro-tumor myelopoiesis.
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