On a daily basis, our microbiome-and the metabolomic networks formed within it-are instrumental in mitigating the body’s inflammatory state, but its composition can be affected by external insults. Lastly, the microbiome is increasingly associated with disease states, including neuropsychiatric and inflammatory bowel diseases, and, as we will discuss, cancer. It is not simply the presence of the microbiome that mitigates these outcomes-specific bacterial genera are responsible for critical functions. The gut microbiome also affects the metabolism of medications, utilizing a wide variety of enzymatic actions including but not limited to reduction, decarboxylation, demethylation, deamination, and hydrolysis of prodrugs. There is increasing study of the microbiome’s role in gluconeogenesis and lipid metabolism.

Specific bacteria in the gut are responsible for digestion and metabolism in a symbiotic manner. The microbiome has already been recognized for its significant role in human metabolism. The microbiome has emerged as a possible therapeutic avenue as well as conduit for understanding mechanisms by which ICI effects are modulated: why do some patients develop crippling toxicities from treatment, while others virtually none? How can we explain the variance in outcomes between patients with similar cancers and tumor PD-L1 expression following treatment with the same drug? Is the oft-noted association between development of irAEs with response to ICI therapy in actuality describing two phenomena that can be decoupled? In short, the current state of immunotherapy in oncology leaves much room for improvement. These phenomena are associated with ICI activation of T cells throughout the body, potentially leading to a multitude of occasionally life-threatening autoinflammatory organopathies. Unfortunately, this suboptimal chance of benefit is accompanied by increased risk of immune-related adverse effects (irAEs). Despite low response rates, patients whose cancers regress under ICI therapy may be more likely to enjoy longer progression-free survival. Save for specific tumor traits such as genomic microsatellite instability (MSI-H), high programmed cell death ligand-1 (PD-L1) expression, or other genetically hypermutated (POLε) states, it appears that only a minority of patients respond to ICI therapy. As indications for immune checkpoint inhibitors (ICI) for treatment of malignancies have broadened, outcomes remain variable and difficult to predict.

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