Fighting in a wasteland: deleterious metabolites and antitumor immunity

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.

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

“…The observation that PDK4 activity is induced during senescence and plays a critical role in promoting natural aging and contributing to age-related physical dysfunction, underscores this enzyme as a valuable target to counteract the overall pathological impact of senescent cells. Chronological age-associated cellular senescence in the tissue microenvironment bridges the gap between high lactate levels, chronic inflammation and pathological events, while accumulation of lactate in solid organs is a pivotal and early event in various diseases 75,76 . Given that high PDK4 expression rewires energy metabolism, holds the potential to cause tissue homeostasis imbalance and overall physical dysfunction, our study raises the possibility that this metabolic kinase is pharmacologically exploited for therapeutic intervention of natural aging and multiple age-related disorders, including but not limited to cancer.…”

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

“…The observation that PDK4 activity is induced during senescence and plays a critical role in forming an acidic microenvironment underscores this enzyme as a valuable target to counteract the overall pathological impact of senescent cells. As of note, acidic microenvironments bridge the gap between high lactate levels, chronic inflammation and pathological events, while accumulation of lactate in solid organs is a pivotal and early event in various diseases 65, 66 . Given that high PDK4 expression causes PDH phosphorylation, rewires energy metabolism, holds the potential to drive tissue homeostasis imbalance and physical dysfunction, our study raises the possibility that this metabolic kinase is pharmacologically exploited for therapeutic intervention of aging and multiple age-related disorders, including but not limited to cancer.…”

The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment

“…Glutamine in the TME also allows T reg cells to accumulate, rather than the Th1 response, if its concentration is limited. Reducing glucose and glutamine in the TME limits UDP-GlcNAc synthesis by T cells and promotes differentiation into T reg rather than Th17 ( Chang et al, 2015 ; Angelin et al, 2017 ; Le Bourgeois et al, 2018 ; Watson et al, 2021 ; Xia et al, 2021 ; Kumagai et al, 2022 ; Watson and Delgoffe, 2022 ). Since cytotoxic cells such as CD8 + T cells and NK cells are sensitive to amino acid restrictions, their function is suppressed when glutamine, serine, and glycine are depleted or when branched-chain amino acids, especially leucine and isoleucine, are restricted ( Gentles et al, 2015 ; Badur and au, 2018 ).…”