Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets

Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.