Table 1.
Possible mechanisms of the influences of gut microbiome on the antitumor efficacy of ICIs.
| Effector component | Effect | Possible mechanism | Model organism | Ref. |
|---|---|---|---|---|
| Bacterial immunostimulants or bacterial antigens | ||||
| Peptidoglycan | Increase | Expression of peptidoglycan hydrolase promotes the generation of muropeptides, which can act as adjuvants through NOD2 receptor. | Mouse B16-F10 melanoma treated with anti-PD-L1, MCA205 fibrosarcoma treated with anti-PD-1, MC38 colorectal carcinoma treated with anti-CTLA-4. | 30 |
| Polysaccharide | Increase | B. fragilis polysaccharides trigger IL-12–dependent Th1 immune responses. | Mouse MCA205 sarcomas treated with anti-CTLA-4. | 24 |
| Exopolysaccharide | Increase | Lactobacillus-derived exopolysaccharides induce CCR6+ CD8+ T cells. | Mouse CCL20-expressing tumor model treated with anti-PD-1 and anti-CTLA-4 (Colon26 colon adenocarcinoma and 4T1 mammary carcinoma). | 31 |
| Type 1 fimbriae adhesion portion | Increase | Escherichia coli adhesion portion FimH induces TLR4-dependent DC maturation. | Mouse CT26 carcinoma treated with anti-PD-L1. | 32 |
| Gut bacterial antigens | Increase | Molecular mimicry between bacteria and tumor-associated antigens may induce cross-reacting CD8+ T cell responses. | Clinical trials of “oncomimic” peptides in combination with anti-PD-1 for treatment of colorectal cancer (NCT05350501). | 34 |
| Bacterial metabolites | ||||
| Butyrate | Increase | Boosting antitumor cytotoxic CD8+ T cell responses through IL-12 signaling pathway. | Mouse MC38 colon carcinoma treated with anti-PD-L1. | 40 |
| Butyrate and propionate | Decrease | Inhibiting anti-CTLA-4-induced DC maturation and T cell priming. | Mouse MC38 and CT26 colon carcinoma and MCA101OVA fibrosarcoma treated with anti-CTLA-4. | 51 |
| Inosine | Increase | Activating anti-tumor T cells through adenosine A2A receptor; serving as an alternative carbon source for CD8+ T cells. | Mouse MC38 colon carcinoma treated with anti-CTLA-4 plus CpG, B16-F10 melanoma treated with anti-PD-L1. | 41, 42 |
| Kynurenine | Decrease | Unknown (higher kynurenine/tryptophan ratio is associated with resistance to anti-PD-1 treatment). | NSCLC patients were treated with anti-PD-1 antibodies. | 50 |
| Trimethylamine oxide (TMAO) | Increase | Induce tumor cell pyroptosis by activating the endoplasmic reticulum stress kinase PERK. | Mouse 66cl4 and 4T1 mammary carcinoma were treated with anti-PD-1. | 43 |
| Anacardic acids | Increase | Unknown (higher levels of anacardic acids in ICI responders). | Metastatic melanoma patients. | 44 |