Manipulation of Metabolic Pathways and Its Consequences for Anti-Tumor Immunity: A Clinical Perspective

Abstract

In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its synergistic potential with immune checkpoint inhibitors (ICIs) in subsequent clinical studies. Looking back from bedside-to-bench, it may not be surprising that the anti-tumor effect of metformin derives largely from its ability to rewire aberrant metabolic pathways within the tumor microenvironment. As one of the most promising breakthroughs in oncology, ICIs were also found to exert their immune-stimulatory effects at least partly via rewiring metabolic pathways. These findings underscore the importance of correcting metabolic pathways to achieve sufficient anti-tumor immunity. Herein, we start by introducing the tumor microenvironment, and then we review the implications of metabolic syndrome and treatments for targeting metabolic pathways in anti-tumor therapies. We further summarize the close associations of certain aberrant metabolic pathways with impaired anti-tumor immunity and introduce the therapeutic effects of targeting these routes. Lastly, we go through the metabolic effects of ICIs and conclude an overall direction to manipulate metabolic pathways in favor of anti-tumor responses.

Keywords: anti-tumor treatment; cancer; glutamine; immune checkpoint inhibitors; immunometabolism; metabolic pathway; metformin; tumor microenvironment.

Figure 1

Various gradients within the tumor microenvironment that are differentially associated with anti-tumor activity and tumor growth. Tumor cells are known for their aberrant metabolic activity that leads to local depletion of a variety of nutrients, including glucose, glutamine, arginine and tryptophan, which effectively hinder anti-tumor activities provided by immune cells that also depend on these nutrients. In addition, metabolites such as lactate, kynurenine and adenosine are released by tumor cells, dampening anti-tumor immunity along with hypoxia.