Figure 2: Cellular metabolism shapes tumor-infiltrating effector T cell responses and differentiation.

a. Effector T cell expansion and function are controlled by glucose metabolism downstream of the AGK–PTEN–PI3K-mTOR signaling axis, which can be antagonized by PD-1 signaling. Further, mitochondrial respiration and metabolism support the function of tumor-infiltrating effector T cells, with metabolites BH4 (synthesized via the enzyme GCH1) and extracellular L-arginine (whose levels are antagonized by methylglyoxal produced by tumor cells) acting as important metabolite regulators of mitochondrial function. Bhlhe40 and BATF are crucial transcriptional regulators of mitochondrial function in tumor-infiltrating T cells, which are inhibited by PD-1 and Regnase-1 signaling, respectively. Cholesterol can also induce the ER stress response–XPB1 signaling axis that suppresses mitochondrial function. Methionine metabolism induced by methionine uptake is crucial to support the effector programming of tumor-infiltrating T cells. b. Stem-like programs that promote T cell longevity and persistence in the TME are programmed downstream of selective metabolic programs. Specifically, the acquisition of stem-like programs is associated with an increase of mitochondrial respiration and spare respiratory capacity (SRC), which can be mediated by glutamine-dependent glutamine metabolism, potassium-induced autophagy, leptin signaling, or fatty acid oxidation (FAO) that is antagonized by MEK signaling. In addition, a stem-like state is adopted upon mitigation of oxidative stress, such as via engaging mitophagy to clear damaged mitochondria or transient glucose restriction.