① It is well known that tumor-associated macrophages (TAM, the most frequent immune cell population in tumors) promote the tumor progression. We have learned that cancer cells consume oxygen and glucose to produce energy. However, TAM are also cells, so shouldn’t TAM also consume oxygen and glucose? If so, how would they co-operate with cancer cells? In our recent research, we found that TAM compete with cancer cells for the oxygen and glucose making tumors more hypoxic and glycolytic. Importantly, with collaboration with clinicians at SNUH, we observed that NSCLC (non-small cell lung cancer) patients with high FDG (fluorine deoxyglucose) PET (positron emission tomography) signals contained higher numbers of TAM and vice versa. We are now expanding this research to other tumor types and other roles that TAM may play in modulating the tumor metabolism. ② We are particularly interested how tumor microenvironment regulates tumor response to radiotherapy (since hypoxia is an ultimate resistance factor to radiotherapy). In our latest paper, we were able to experience the latest radiotherapy technique, called FLASH radiotherapy, developed by Prof. Billy Loo at Stanford University. They’re delivering high dose of ionizing radiation at the ultra-fast speed (at least 20 times faster than conventional radiotherapy technique), lowering the normal tissue toxicity significantly. We found that FLASH irradiation also produces very interesting changes in the tumor microenvironment compared to conventional irradiation. ③ We are also interested in investigating how macrophages sense hypoxia. Cells usually activate a transcription factor called hypoxia-inducible factor (HIF) under hypoxic conditions to turn on many genes involved in survival/death/cell cycle arrest, adaptation to hypoxia, and angiogenesis. In our lab, we have knockout mice targeting HIF pathways only in macrophages. In our recent papers, we have challenged these mice to cerebral ischemia (stroke model through middle cerebral artery ligation), hindlimb ischemia (through femoral artery ligation), and inflammatory bowel disease to study interesting and disease-specific role of HIF in macrophages. We are now investigating the role of HIF in macrophages in regulating diet-induced obesity.