RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression

Abstract Despite well-documented metabolic and hematopoietic alterations during tumor development 1 , the mechanisms underlying this crucial immunometabolic intersection have remained elusive. Of particular interest is the ligand-activated transcription factor retinoic acid-related orphan receptor 1 (RORC1/RORγ), whose activity is boosted by cholesterol metabolites 2 , acting as a modulator of cancer-related emergency myelopoiesis 3 , while hypercholesterolemia itself is associated with dysregulated myelopoiesis 4,5 . Here we show that both cancer growth and hypercholesterolemic diet can independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2 polarization of tumor-associated macrophages (TAMs), thereby supporting cancer spread. Moreover, we report that tumor development enhances the hepatic production of IL-1β and IL-6, which in turn promote upregulation of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, as we confirmed in models of fibrosarcoma, melanoma, colorectal (CRC), and lung cancer, as well as in CRC, non-small-cell lung cancer (NSCLC), breast (BRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract carcinoma (BTC) and pancreatic neuroendocrine tumor (PNET) patients. Importantly, lowering cholesterol levels prevents MDSC expansion and M2 TAM accumulation in a RORγ-dependent manner, unleashing specific anti-tumor immunity and improving the efficacy of anti-PD-1 immunotherapy. Overall, we identify RORγ as a novel sensor of lipid disorders in cancer bearers, bridging hypercholesterolemia and pro-tumor myelopoiesis.