What aspect of tumor metabolism is most promising in terms of a target for novel cancer therapy or immunotherapy?

Immune effector cell therapies have huge therapeutic potential and can prolong lives of cancer patients. Yet we have much to learn about preparing products with long lasting anti-tumor activity and memory functions. Metabolic intervention during cell manufacture may help produce fitter cells with enhanced expansion, function and persistence upon adoptive transfer, even in tumors with complex microenvironments.

Strategies to starve cancer of energy, like mitochondrial uncoupling drugs or very low-carbohydrate diets. We recently discovered that tumors make cellular energy much slower than most healthy tissues, meaning that tumors live and proliferate using an extremely tight energy budget. When cancer starvation is combined with chemotherapy or radiation, starved cancer cells may not have the energy to repair the damage.

Tumor cells fiercely compete with T cells for a limited supply of nutrients that are needed as ‘building blocks’ or as energy sources. One promising approach to improving adoptive T cell therapy (ACT) is to engineer T cells to boost their metabolic fitness. For example, we enforced expression of the high affinity glucose transporter GLUT3 in cytotoxic T lymphocytes and demonstrated that the cells had higher energy storage and superior ability to control tumors when they were used for ACT.

Tumor metabolism provides intrinsic and extrinsic support for tumor outgrowth and immune evasion. Elucidating the metabolic processes and underlying mechanisms by which tumor cells disarm anti-tumor immunity will be a springboard for the development of new cancer immunotherapies.

It is hard to pick a single target. This field is blossoming with many promising ideas and targets. One area in particular our team is excited about is lipid metabolism. Cancer biologists have learned much about how lipid metabolism is rewired in many tumors, especially those that become metastatic and therapy resistant. I think the field is primed to translate this knowledge into new therapeutics.

The aspect of tumor metabolism that I find most intriguing is the competition between the tumor and the immune system for nutrients at the tumor site. From glucose to amino acids, a decisive element for immunotherapy success is the ability to fuel the anti-cancer response and overcome those metabolic checkpoints encountered. A promising therapeutic strategy would be to modulate the ability of cellular immunotherapies to take up essential molecules, thereby enabling the therapies to reach their full potential in the harsh tumor microenvironment.

Augmenting nutrient availability to tumor-fighting T cells. The tumor metabolic microenvironment is depleted in critical nutrients, including oxygen, glucose, glutamine and nucleotide precursors. Bolstering these helps T cells fight tumors. For example, we’ve recently found synergy in mice between checkpoint blockade and dietary supplementation with one-carbon units, a key feedstock of nucleotide synthesis.