Table 1. Hostile Conditions in The Tumor Microenvironment Impair T Cell Metabolism and Anti-Tumor Immunity.

Cancer cell metabolism, improper blood vessel formation, and extracellular vesicles all contribute to a toxic milieu deficient in key nutrients, such as glucose and oxygen, and high in waste products, such as lactate. Consequently, TILs entering the TME are deprived of key nutrients, disturbing metabolic processes critical for their anti-tumor functions.

Component of the TME	Impact on T Cell Metabolism	Effect on Anti-Tumor Immunity
Hypoxia	• Stabilizes HIF-1α • Increases pyruvate dehydrogenase kinase, blocking the conversion of pyruvate to acetyl-CoA and thus mitochondrial respiration and ROS production • Increases lactate dehydrogenase A expression and inactivates pyruvate dehydrogenase, shunting pyruvate to lactate	• Increases granzyme B packaging into granules, leading to rejection of B16 tumors in mice • Upregulates PD-L1 expression on MDSCs • Decreases T cell infiltration
Depletion of Glucose	• Reduces aerobic glycolysis • Decreases levels of phosphoenolpyruvate, which regulates calcium and NFAT signaling	• Suppresses TIL effector function • Reduces EZH2 expression, decreasing T cell polyfunctionality
Accumulation of Lactate	• Impedes lactic acid export from CD8+ T cells, which slows down glycolysis and reduces ATP levels • Decreases NFAT levels and translocation to the nucleus	• Inhibits T cell proliferation, activation, and function • Induces T and NK cell apoptosis
Tumor-derivedExtracellular Vesicles (EVs)	• Modulates the metabolism of tumor associated macrophages and other cell types. • Effects of EVs on T cell metabolism are currently unknown	• Suppresses TIL anti-tumor function. • However, blocking EV biogenesis induces T cell activation, proliferation, and effector function.