T cells require both costimulatory and coinhibitory to regulate their functions and differentiation states. Recently, these comodulatory signals have been shown to also reprogram T-cell metabolism. T cells require optimal costimulation signals for activation, proliferation, and differentiation to effector T cells, to induce an effective antitumoral response. Costimulatory molecules promote anabolic pathways to synthesize proteins and lipids so that T cells produce the required molecules and structures to perform their functions. On the other hand, coinhibitory signals, which are required to regulate T-cell functions and maintain homeostasis, are frequently deregulated in cancer. Coinhibitory signals tend to promote catabolic pathways, favoring a low rate of nutrient consumption. Comodulatory signals have been subjected to intense research for developing immunotherapies against cancer, a strategy known as checkpoint immunotherapy. Thus, the characterization of the mechanisms by which these signals modulate T-cell metabolism has become of great relevance. The present chapter summarizes the main comodulatory molecules that regulate T cells, their effects on metabolism, and the implications for checkpoint immunotherapy.