Inhibition of PFKFB3 in Macrophages Has a Dual Effect on Tumor-Regulating Lipid Metabolism

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Abstract
Colorectal cancer is the third most common cancer worldwide, making lymph node recovery critical for treatment decisions and prognosis. Within the colorectal tumor microenvironment, the metabolic programming of tumor-associated macrophages (TAMs) can drive both pro- and anti-tumor responses, yet the specific glycolytic pathways governing their pro-metastatic conversion present promising therapeutic targets. This study investigated the role of glycolysis activating enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in mediating TAMs metabolic polarization, and its potential as a therapeutic target. PFKFB3 expression was found to be predominant in TAMs in CRC tumor samples. Lipidomic analysis performed by HPLC-MS/MS revealed that PFKFB3 inhibition altered glycerophospholipid metabolism (p = 6.13 × 10−10), and shifted TAMs toward sphingolipid-mediated immunosuppressive metabolism. PFKFB3 activity was associated with a specific reduction in asparagine availability, potentially pointing to a targeted reprogramming of amino acid metabolism supporting distinct TAM functions under conditions of intra-tumoral metabolic stress. These findings highlight PFKFB3 as an essential regulator of TAMs pro-tumoral metabolism in CRC, particularly in colon cancer.
Funding Information
  • Russian Science Foundation (24-25-00455)

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