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Fighting in a wasteland: deleterious metabolites and antitumor immunity
McLane J. Watson, Greg M. Delgoffe
McLane J. Watson, Greg M. Delgoffe
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e148549. https://doi.org/10.1172/JCI148549.
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Review Series Article has an altmetric score of 11

Fighting in a wasteland: deleterious metabolites and antitumor immunity

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Abstract

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.

Authors

McLane J. Watson, Greg M. Delgoffe

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Figure 2

Metabolic alteration of the TME to improve cancer immunotherapy.

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Metabolic alteration of the TME to improve cancer immunotherapy.
Alterat...
Alteration of the metabolic landscape of the tumor can be accomplished in many ways. Lactic acid production by tumor cells can be targeted using an inhibitor of LDH (GSK2837808A). Alternatively, lactic acid export by tumor cells could be targeted using MCT1 inhibitors (AZD3965 in clinical trials, 7ACC2 and AR-C155858 in preclinical work) or MCT4/MCT1 dual inhibitors (syrosingopine). MCT1 inhibitors may also block Treg import and usage of lactic acid, leading to diminished suppressive function and proliferation. Lactic acid lowers the pH of the TME, which can be counteracted through bicarbonate treatment. Tryptophan depletion and kynurenine production can be targeted by inhibition of IDO found on tumor cells and TAMs (epacadostat, indoximod, GDC-0919). Alternatively, kynurenine alone can be depleted using an enzyme engineered for its degradation (PEGylated kynureninase). Oxygen depletion can be targeted using VEGF inhibitors (bevacizumab) or VEGFR inhibitors (axitinib) to normalize tumor vasculature and improve tumor oxygenation. Metformin, a common diabetes drug, can be used to decrease tumor hypoxia, potentially through its action as a mitochondrial complex I inhibitor. ROS can be targeted through drugs promoting endogenous ROS scavengers (RTA-408 promoting Nrf2) or by addition of exogenous engineered ROS nanoscavengers. The production of adenosine can be targeted using monoclonal antibodies against CD39 (TTX-30) and CD73 (both membrane bound and soluble [sCD73]; oleclumab) or by small-molecule inhibition of the A2AR (ciforadenant).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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