Figure 4.

Linking radiotherapy resistance and serine/glycine metabolism in the tumor and associated tumor microenvironment. Activation of de novo serine/glycine biosynthesis pathway in cancer stem cells (CSC) under hypoxia and nutrient-deprived conditions is important to sustain cancer cell viability and proliferation, supporting the synthesis of nucleotides for DNA repair, as well as the synthesis of reductive equivalents that protect the cancer stem cells and their progeny against redox stress via autocrine and paracrine routes. In addition, de novo serine/glycine biosynthesis enzymes, i.e., PHGDH and PSAT1, are involved in the maintenance of CSCs stemness and self-renewal, for instance, via posttranslational regulation of OCT4, as well as regulating stem cell fate via αKG. In the tumor microenvironment, high PHGDH activity is essential for the survival of endothelial cells and promotes an immunosuppressive microenvironment with an increase in M2 macrophage polarization. In addition, serine and glycine are required for the expression of the pro-inflammatory cytokine IL-1β.