As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, “toxic” metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies.
