Figure 5.

Future perspectives overview implicating serine/glycine metabolism-targeted therapies in combination with radiation therapy. The rational integration of serine/glycine metabolism-targeted therapies in combination with radiotherapy is important to optimize the efficacy and enhance the therapeutic ratio of radiotherapy. The stratification methods to select patients that might benefit from these combined treatment modalities could include the analysis of serine, GSH, or methionine serum levels or the expression of de novo serine/glycine biosynthesis enzymes. The therapeutic strategies targeting serine/glycine metabolism include limiting the availability of exogenous serine by diet restriction and targeting the enzymes of de novo serine/glycine biosynthesis pathways, for instance, SHMT inhibition using sertraline. In addition, mitochondrial inhibitors, e.g., metformin, phenformin or artemether, might have synergistic antitumor effects in combination with serine/glycine-targeted strategies and enhance the response to radiotherapy. Finally, targeting serine/glycine metabolism before radiotherapy, concomitantly or sequentially, requires considering serine/glycine metabolism functions in cancer cells and the tumor microenvironment and how targeting this metabolic pathway might enhance or counteract the response to radiotherapy. The blue arrows indicate expected cellular changes, in green beneficial outcome of the cellular changes and in orange the limitations of the outcomes related to the cellular changes.