Abstract
Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.
Highlights
Cancer immunotherapies are paradigm-shifting drugs employed to augment the host antitumor immune response to treatment
The subset of immunotherapies known as immune checkpoint inhibitors (ICI) promote effective antitumor immunity by relieving suppressive effects induced by various immune checkpoint signaling pathways in T cells
Immune checkpoints refer to numerous inhibitory pathways found in immune populations that are critical to self-tolerance and modulation of the immune response [137]
Summary
Cancer immunotherapies are paradigm-shifting drugs employed to augment the host antitumor immune response to treatment. The TME is metabolically hostile to immune cells, in part due to the existence of significant competition between various cell types for a limiting nutrient pool [5] Such aberrant metabolite abundance is further compounded by inefficient tumor vasculature, resulting in frequent zones of hypoxia and differential metabolism [6]. We considered the role of microenvironment nutrient profiles in shaping tumor immune surveillance and the potential for crosstalk between immunotherapy, cell metabolism, and energy balance. To execute their function, immune cells undergo rapid, phenotypic shifts in response to stimuli in their environment. This review aimed to examine the metabolic determinants of ICI response, both immune cell-intrinsic and extrinsic, including TME nutrient availability and metabolic mechanisms through which tumor cells evade immune surveillance
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