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 1

Mechanisms of gut bacteria–mediated antitumor immunity.

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Mechanisms of gut bacteria–mediated antitumor immunity. (A) E. faecium, ...
(A) E. faecium, E. hirae, E. durans, and E. mundtii release orthogolgs of SagA, a peptidoglycan hydrolase that breaks muramyl bonds in peptidoglycan of other gut bacteria to release GMDP. GMDP signals through NOD2 on myeloid cells to increase transcription of IL-1b and NLRP3 and increase granzyme B+ (GZMB+) CD8+ T cells in the tumor (7). Whether GMDP released by gut bacteria travel from the tumor or immune cells from the gut that have been exposed to GMDP travel to the tumors is unknown. (B) C. cateniformis contains a surface metabolite that suppresses PD-L2 expression on MHCII+CD11b+ and MHCII+CD11c+ immune cells in the mesenteric and tumor-draining lymph nodes (MLNs and dLNs). Blockade of PD-L2/RGMb interactions increases tumor-infiltrating GZMB+ and IFN-γ+CD8+ T cells in the tumors to promote antitumor immunity to anti–PD-L1 (8). How C. cateniformis suppresses PD-L2, whether the microbial surface metabolite or cells that interact with C. cateniformis travel to the dLN, and how the gut microbiome impacts RGMb expression are unknown. (C) A. mucinophila and other bacteria that increase in abundance on a high-fiber diet release c-di-AMP and other products. These products signal through cGAS/STING in monocytes, stimulating antitumor macrophages and releasing type 1 IFNs that stimulate NK cells to release XCL1 and CCL5 and increase tumor-infiltrating dendritic cells to release IL-15 and its receptor IL-15RA. This monocyte-NK-DC crosstalk promotes antitumor responses to anti–PD-1 (55). Whether microbially derived STING agonists or monocytes that have interacted with microbially derived STING agonists in the gut travel to the tumors is unknown. (D) Gut bacteria sensitive to oral metronidazole release TMA, which gets converted into TMAO in the liver, enters the blood stream, and stimulates tumor-associated macrophages to increase IFN-γ+ TNF-α+ CD8+ and CD4+ T cells in the tumor in a type 1 IFN-dependent manner; this increases response of pancreatic ductal adenocarcinoma (PDAC) tumors to anti–PD-1 therapy (40). (E) L. rhamnosus GG was also shown to signal through cGAS/STING on dendritic cells to release IFN-β and increase IFN-γ+CD8+ T cells in tumors, promoting antitumor immunity to anti–PD-1 treatment (10). The identity of the microbial metabolite from L. rhamnosus GG, and whether the metabolite or cells that interacted with L. rhamnosus GG travel from the gut to the tumor, are unknown. Furthermore, it is unclear why L. rhamnosus GG promotes antitumor immunity in some conditions, but not others (10, 14).