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Background Cancer-related inflammation promotes the expansion of immunosuppressive myeloid cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which support tumor progression and immune evasion. These alterations are often associated with lipid and cholesterol dysregulations. However, the mechanistic links between lipid metabolism and tumor-induced myelopoiesis remain elusive. The nuclear receptor Rorc/RORγ, a transcriptional regulator of emergency myelopoiesis, is activated by cholesterol metabolites. In parallel, PCSK9, a hepatic regulator of cholesterol homeostasis, has emerged as a potential immune modulator in cancer. This study investigated how tumor-derived inflammation (i.e., IL-1β and IL-6) and dietary lipids drive a PCSK9-cholesterol-RORγ axis that promoted immunosuppressive myeloid cell expansion.Methods We employed multiple syngeneic tumor models (fibrosarcoma, melanoma, colon, lung) and a KRAS/p53-driven genetically engineered lung adenocarcinoma (KP) model to assess serum cholesterol, LDL, and PCSK9 levels under standard or high-cholesterol diets. Hepatic/systemic PCSK9, as well as IL-1β and IL-6 levels were evaluated in both mice and cancer patients. Therapeutic interventions included anti-IL-1β, anti-IL-6, and anti-PCSK9 antibodies, as well as hematopoietic PCSK9 deficiency, myeloid-specific RORγ deletion (Rorc fl/fl Lyz2-Cre) or RORγ pharmacologic inhibition (SR2211). Immune profiling was performed via flow cytometry and gene expression; functional assays measured T cell suppression by tumor-infiltrating myeloid cells. Blood samples from cancer patients (lung, colorectal, breast, pancreatic, biliary, neuroendocrine tumors) were analyzed for cholesterol and PCSK9 levels and RORγ+ myeloid cells accumulation. Anti-PD-1 efficacy was tested in combination with RORγ inhibitor SR2211.Results Both tumor-bearing mice and patients displayed elevated total/LDL cholesterol and PCSK9, which were exacerbated by high-cholesterol diets. Tumor-derived IL-1β and IL-6 induced hepatic PCSK9 expression, impairing LDL clearance and linking inflammation to cholesterol dysregulation.Both cancer and hypercholesterolemic diet independently or synergistically promoted RORγ-dependent accumulation of MDSCs and M2-polarized TAMs across primary and metastatic sites. In NSCLC patients, cholesterol levels positively correlated with circulating RORγ+ monocytic-MDSCs. Lipidomic profiling showed TAMs enriched in triglycerides and cholesterol, promoting M2 polarization. Blocking IL-1β/IL-6 reduced PCSK9 and cholesterol levels and, eventually, immunosuppressive RORγ+ myeloid cells. Inhibiting PCSK9 or RORγ constrained MDSC and M2 TAM expansion and tumor growth in both fibrosarcoma and KP models. These effects were abolished in Rorc fl/fl Lyz2-Cre or PCSK9-null mice. Notably, SR2211 enhanced anti-PD-1 efficacy.Conclusions We identified a tumor- and lipid-driven immunometabolic circuit in which PCSK9 promotes RORγ-dependent suppressive myelopoiesis. Targeting this axis limits tumor-supportive myeloid cells and enhances immunotherapy, supporting the PCSK9-cholesterol-RORγ pathway as a therapeutic target in cancer.