The gut microbiome and cancer response to immune checkpoint inhibitors
Francesca S. Gazzaniga, Dennis L. Kasper
Francesca S. Gazzaniga, Dennis L. Kasper
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e184321. https://doi.org/10.1172/JCI184321.
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Review Series

The gut microbiome and cancer response to immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don’t respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.

Authors

Francesca S. Gazzaniga, Dennis L. Kasper

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Figure 2

Gut bacterial metabolites that directly impact T cells in tumors.

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Gut bacterial metabolites that directly impact T cells in tumors. (A) B....
(A) B. pseudolongum releases inosine. Upon treatment with anti–CTLA-4, inosine enters the bloodstream and signals through the adenosine receptor (A2A) to increase IFN-γ+CD4+ and CD8+ T cells to promote response to anti–CTLA-4 (13). (B) L. reuteri releases indole-3-aldehyde (I3A), which enters the bloodstream and signals through the aryl hydrocarbon receptor (AhR) to promote tumor-infiltrating GZMB+ and IFN-γ+CD8+ T cells and increase response to anti–PD-L1 treatment (54). L. reuteri also appears to translocate to the tumor to promote antitumor immunity, though how it translocates to the tumor without inducing an infection response is unknown (54). (C) L. gallinarium produces indole-3-carboxaldehyde, which gets converted in the serum to indole-3-carboxylic acid (ICA), which blocks kynurenine (Kyn) signaling through the AhR receptor. This decreases the amount of tumor-infiltrating Tregs, resulting in more IFN-γ+CD8+ T cells in the tumors; this in turn promotes antitumor responses to anti–PD-1 therapy in tumors implanted subcutaneously and in tumors arising in the gut by AOM/DSS-induced colitis (9). (D) In tumors in the colon, R. intestinalis releases butyrate that signals through TLR5 to induce IFN-γ+CD8+ T and increases response to anti–PD-1 treatment. Whether this mechanism works in tumors outside of the gut remains unclear (11).