A hallmark of cancer cells is altered metabolic
programming. Cancer cells are directed by
signals from each other and from stromal
sources to prefer anaerobic to catabolic
energy-producing processes7, 8. This gives them
multiple energy production options, including
lactate, acetate, ketone bodies, and ammonia
metabolism pathways7, 9. They take up and use
more glucose than healthy cells^7. The resulting
rapid AT P generation enables elevated rates
of proliferation and allows cancer cells to
outcompete other cells for resources7, 9. Finally,
cancer cell metabolic pathways also secrete
immuno-suppressive metabolites such as
prostaglandin Eā and kynurenine^9.Metabolic
Reprogramming
Gives Cancer
Cells Advantages
The metabolic differences between cancer and healthy cells present opportunities for researchers to
target the former without overly impacting the latter. However, directly blocking glucose metabolism
involves navigating a fine line between efficacy and hypoglycemia; this has led scientists to target
other pathways, such as fatty acid synthesis and NAD+/NADH homeostasis^10. In addition, the elevated
metabolic and proliferation rates of cancer cells make them susceptible to oxidative stress-induced
apoptosis and DNA synthesis inhibitors10,11.Starving Cancer
into Submission
The acidic TME induces genomic instability, leading to more oncogenic mutations and creating more
aggressive tumors. This also stimulates invasion and metastasis. Attempts to directly alter TME
pH using buffer solutions have proven difficult to translate to the clinic. Scientists have therefore
focused their efforts on inhibiting metabolic pathways that create acidic byproducts. However,
targeting compounds that create alkaline products or absorb acidic ones have demonstrated some
feasibility in clinical testing^15.Neutralizing Acidosis
Activated T cells rely on aerobic glycolysis to function, so they directly compete with cancer cells for
resources^12. As such, inhibiting cancer cell energy production can restore immune function. In order to
avoid side effects on immune cells, scientists are looking for metabolic targets, pathways, and
transporters selectively used only by cancer cells. One example of this is EphA2, which promotes
glutamine metabolism in breast cancer cells but is not expressed by T cells13,14. Alternatively, modulating
immune cells ex vivo to make them more metabolically fit could improve functional efficacy^12.Fueling Immune Responses