Metabolic Reprogramming of Neutrophils by Tumor-Derived Lactate

Tumor-associated neutrophils (TANs) are pivotal regulators within the tumor microenvironment (TME), where their functional plasticity is significantly influenced by metabolic cues. This study investigates the role of lactate and palmitic acid in modulating the phenotype of HL-60-derived neutrophil-like cells. We demonstrate that lactate induces a dose-dependent upregulation of Ki-67 protein and mRNA, correlating with enhanced cellular proliferation. Notably, lactate—but not palmitic acid—significantly promoted the transcription of immunosuppressive markers CD206 and Arg1, indicating a shift toward a pro-tumor N2-like TAN phenotype. Mechanistically, lactate exerted its effects through transcriptional activation, while palmitic acid functioned post-transcriptionally. Functional assays revealed that lactate (100–200 μM) increased cell proliferation, whereas higher concentrations (≥10 μM) induced cytotoxicity after prolonged exposure, highlighting a concentration- and time-dependent dichotomy. Transwell assays confirmed neutrophil chemotaxis and ECM-invasive capacity. These findings underscore lactate’s role as a master regulator of neutrophil proliferation and immunosuppressive polarization. Our results provide new insights into the metabolic reprogramming of TANs and suggest that targeting lactate signalling may offer a viable strategy to counteract neutrophil-mediated immunosuppression in cancer.