Immunometabolism and Its Potential to Improve the Current Limitations of Immunotherapy

The last century of research in tumor immunology has culminated in the advent of immunotherapy, most notably immune checkpoint inhibitors. These drugs have shown encouraging results across a multitude of malignancies and have shifted the paradigm of cancer treatment. However, no more than 40% of patients treated with these immune checkpoint blockade inhibitors respond. Thus, resistance is a barrier to therapy that remains poorly understood. All cells require energy and biosynthetic precursors for survival, growth, and functioning, where multiple metabolic pathways allow for flexibility in how nutrients are utilized. A defining hallmark of many cancers is altered cellular metabolism, creating an imbalanced demand for nutrients within the tumor microenvironment. Immunometabolism is increasingly understood to be vital to the functions and phenotypes of a myriad of immune cell subsets. In tumors, the high demand for nutrients by the tumor drives competition between tumor cells and infiltrating immune cells, culminating in dysfunctional immune responses. This chapter discusses the recent successes in cancer immunotherapy and highlights challenges to therapy. We also outline the major metabolic processes involved in the generation of an immune response, how this can become dysregulated in the context of the tumor microenvironment, and how this contributes to resistance to immunotherapy. Finally, we explore the potential for targeting immunometabolic pathways to improve immunotherapy, and examine current trials targeting various aspects of metabolism in an attempt to improve the outcomes from immunotherapy.