Laura V. Pinheiro1,2,3,4, Pedro Costa-Pinheiro1,3,4 and Kathryn E. Wellen1,3 1Department of Cancer Biology, Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA 2Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA 3Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA Correspondence: wellenkupenn.edu

↵4 These authors contributed equally to this work.

Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.