Fig. 3

T cell differentiation is accompanied by metabolic changes, which can be affected by the tumor microenvironment altering their fate and function. a Naïve T cells function in antigenic surveillance and do not proliferate. This requires minimal energetic and biosynthetic activity which is represented by a metabolically quiescent state which is accompanied by minimal nutrient uptake. The only energy-demanding processes are ion homeostasis, membrane integrity, and movement. The primary ATP sources are OXPHOS and FAO to fuel the low energy demand. IL-7 signaling and activation of PI3K-Akt1-mTOR is required for survival and basal, low level Glut1 expression. (Furthermore, naïve T cells express low levels of both isoforms of PKM1 and PKM2 keeping PKM2 oncogenic function in check. Low quantities of pyruvate and glutamine are utilized in the TCA cycle. b Upon antigen encounter T cells differentiate into effector cells. This process is accompanied by metabolic changes which are required to fulfill the new effector functions and rapid proliferation. Antigen binding to the TCR and co-activation by CD28 inhibits FAO and activates PI3K-Akt1. This activation triggers glycolytic enzymes HK and PFK2. Additionally, mTOR signaling is turned on which enhances expression of glycolytic genes, glucose, and amino acid transporters via activation of transcription factors HIF1α and Myc. Effector T cells also switch from balanced PKM1 and PKM2 expression to increased and predominant expression of PKM2, which promotes generation of biosynthetic precursors. Additionally, the SRC is decreased and the uptake of nutrients is enhanced. These events promote the establishment of a glycolytic phenotype with increased glutaminolysis combined with a high degree of protein, lipid, and nucleic acid synthesis to support cell growth and proliferation. c After antigen challenge most effector T cells undergo apoptosis during the contraction phase. A small proportion differentiates into memory T cells with prolonged survival capacity to provide long-term antigenic memory. Memory T cells do not proliferate and thus have minimal biosynthesis and nutrient uptake. However, they show increased SRC, which supports their ability to rapidly proliferate upon re-encounter of antigen. This cellular fate includes another metabolic adaption. In particular, metabolic switch to FAO via increased CPT1 expression and elevated AMPK activity, which represses HIF1α, mTOR, and Myc. Thereby, AMPK inhibits glycolysis, which was the primary ATP source during the effector phase. Extracellular queues that support memory cell formation -such as IL-15- promote these metabolic changes. Naïve T cells can differentiate into different subsets of specialized T cells mainly depending on extracellular stimuli and factors. The tumor microenvironment influences these cell fate decisions in a metabolic manner. The lack of glucose, amino acids, and oxygen as well as the accumulation of metabolic byproducts secreted to the microenvironment generate a milieu that suppresses glycolysis-dependent T cell fates like CD8⁺ T effector cells and CD4⁺ Th1/2/17. In contrast, FAO-related cell fates such as CD8⁺ T cell memory and CD4⁺ T regulatory cells are promoted. Especially, amino acid depletion supports formation of immunosuppressive macrophages. Taken together, the tumor microenvironment generates an immunosuppressive milieu that fosters immune evasion