Lactic acid promotes an MDSC-like phenotype via HIF1α stabilization with impact on prognosis in renal cell carcinoma

Paradoxically, immune cell infiltration correlates with worse prognosis in renal cell carcinoma (RCC) patients, with tumor-associated myeloid cells playing a key role in tumor progression. However, little is known about factors driving their polarization. Here, we investigated the link between RCC-related glycolysis, hypoxia-inducible factor (HIF)1α-associated myeloid inflammation, and patient prognosis. TCGA data revealed a strong correlation between the expression of monocarboxylate transporter 4 (MCT4), the myeloid marker CD14 and patient survival in ccRCC patients. scRNAseq data confirmed high MCT4 expression in both tumor and myeloid cells, suggesting lactate transport. In vitro analyses proved lactate uptake by CD14⁺ monocytes, which stabilized HIF1α and induced an MDSC-like, HLA-DR low phenotype. In line, the HIF1α-stabilizing drug Roxadustat increased the number of CD14⁺ HLA-DR low cells. Lactate uptake also increased protein lactylation. To further investigate the interplay between RCC tumor and myeloid cells, we established a 3D spheroid co-culture model and analyzed the effects of MCT inhibitors. This 3D model reflected tumor-myeloid cell interactions, as spheroid-infiltrating myeloid cells exhibited spontaneous IL-6 secretion comparable to patient-derived RCC cultures. Inhibition of lactate secretion reduced lactate and IL-6 secretion while increasing CD14⁺ HLA-DR⁺ cells. These findings were validated in patient-derived RCC cultures treated with anti-glycolytic drugs. Our data dissect the intratumoral network of RCC and show that tumor-derived lactate promotes a pro-tumorigenic myeloid phenotype with low MHC-II but high immune-checkpoint, LOX-1 and S100A8/9 expression. Blocking MCT disrupts this interplay, offering a promising strategy to re-educate tumor-associated myeloid cells and enhance tumor immune surveillance.