Fig. 2

Cancer cells induce several metabolic changes in the microenvironment. The increased uptake of nutrients such as glucose and amino acids depletes these resources for non-tumor cells. This can inhibit the growth and function of non-tumor cells in the microenvironment due to the lack of resources for cellular metabolism. Moreover, nutrient depletion can lead to autophagy, ER-stress, and, finally, to cell death. Cancer cells also generate a hypoxic microenvironment. The prolonged lack of oxygen inhibits regular cell function in non-tumor cells, whereas in cancer cells hypoxia (in combination with oncogenic PI3K signaling) stabilizes HIF1α and promotes the glycolytic phenotype. Additionally, HIF1α enhances expression of PDL-1, which can engage with PD-1 on other cancer cells in the microenvironment. This activates mTOR signaling and supports tumor growth, whereas engagement of PD-1 in T cells inhibits T cell activation and growth. Thereby, cancer cells can spread an inter-cancer-cell growth signal, while suppressing responses of tumor-infiltrating T cells. The increased metabolic activity of cancer cells produces waste byproducts, like lactate and tryptophan metabolites, which are secreted to the microenvironment and act inhibitory on non-tumor cells. Lactate not only acidifies the microenvironment resulting in inhibition of the surrounding non-tumor cells, but can also be re-imported into cancer cells and can be used to feed into glycolysis