Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Stanley (Ching-Cheng) Huang, PhD

Mentor Alex Huang, MD, PhD
Award Type Career Development Award
Institution Case Western Reserve University

While significant progress has been made in developing new therapeutics to control melanoma, the promising clinical outcomes of immune checkpoint inhibitors have drastically shifted the paradigm of cancer treatment. However, a high rate of primary resistance impedes the efficacy of checkpoint inhibitor treatments. Therefore, there is an urgent need for a more detailed understanding of how immune cells govern melanoma progression, as it provides a critical foundation for developing novel interventions and targets to enhance current melanoma immunotherapies. Macrophages are the frontline soldiers of the immune system. Their role is to reduce pathogenic insults and alert other immune cells to an external attack. Macrophages need to adopt different types of defense modes (or armors) in order to carry out their diverse functions, from combating the different types of invading pathogens to fighting cancer. These modes are referred to as pro-inflammatory M1 and anti-inflammatory M2. It was recently found that changes in cell-intrinsic and extrinsic metabolism can alter the immunity mode adapted by macrophages to respond to the pathogenesis of cancer but the mechanism underlying decision-making is still elusive. We propose that an important metabolic network called “serine one-carbon metabolism” plays a crucial role in M2 macrophages, and can be controlled to win the fight against melanoma. By investigating this and the different ‘forces’ that shape macrophage immunity, we hope to understand how macrophages decide to choose their armor to eliminate cancer. The ultimate aim is the ability to harness macrophage immunity to develop new and effective immunotherapies for melanoma.