Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC. Glutamine metabolism in TAMs: targeting HIF-1α translation for HCC This research examines how a substance derived from glutamine (an amino acid) called aspartate influences tumor-associated macrophages (TAMs - immune cells found in many cancers). Led by Dr. Keun-Gyu Park, the team discovered that aspartate from glutamine encourages TAMs to support the growth of hepatocellular carcinoma (HCC - a liver cancer). This process is aided by a protein, eIF5A. The team performed tests on mice and human cells and studied tissue samples from HCC patients. They discovered that blocking eIF5A’s function in TAMs could halt tumor growth. The research suggests that focusing on this metabolic process in TAMs could be a potential treatment strategy for HCC. The results also hint at possible future applications for treating other cancers. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.