Table 2 Reports on microbial metabolites that affect immunotherapy

Triple-negative breast cancer (TNBC)

αPD-1 mAb

Trimethylamine N-oxide (TMAO)

Clostridiales

PERK

TMAO induced tumor cell pyroptosis by activating ER stress kinase PERK, thus enhancing antitumor immunity mediated by CD8⁺ T cells

[135]

PDAC

αPD-1 mAb and/or αTim-3 mAb

Trimethylamine N-oxide (TMAO)

TMAO induced an immunostimulatory phenotype in macrophages, which supported effector T-cell responses in a type I IFN-dependent manner and facilitated the efficacy of αPD-1 or αTim-3 mAb

[136]

ICI-induced colitis

αCTLA-4 mAb

Indole-3-carboxaldehyde (3-IAld)

AhR

3-IAld activates AhR/IL-22 dependent signaling pathways in the host, controls colon inflammation induced by αCTLA-4 mAb therapy, and reduces adverse reactions associated with ICB therapy by altering the composition and function of the gut microbiota

[143]

Lymphoma (EL4); CRC (MC38); breast cancer (TUBO); melanoma (BRAF^V600E/PTEN^−/−)

αPD-1 mAb; αPD-L1 mAb

STING agonists, including c-di-AMP

Akkermansia muciniphila

STING signaling pathway

STING agonists generated by bacterial metabolism such as c-di-AMP induce intratumoral monocytes to produce type I IFN, thus promoting the polarization of tumor suppressor macrophages and antigen presentation between NK cells and DC cells, which promotes antitumor immunity

[144]

HNSCC

αPD-L1 mAb

Bacterial lipopeptide Pam3CSK4

Staphylococcus aureus

TLR2

Bacterial lipopeptide Pam3CSK4 enhances the expression of PD-L1 in multiple HNSCC cell lines and directly promotes immunosuppression

[145]

Hepatocellular carcinoma (HepG-2)

γδT immunotherapy combined with antibiotics

3-Indolepropionic acid (IPA)

IPA can stimulate γδT cells to release more cytotoxic cytokines, such as granzyme B and perforin, thus improving the efficacy of immunotherapy

[146]

CRC (AOM-DSS/MC38); bladder cancer (MB49); melanoma (B16-F10)

αCTLA-4 mAb

Inosine

Bifidobacterium pseudolongum; Lactobacillus johnsonii; Olsenella species

A_2A receptor

Inosine produced by the gut microbiota can translocate to the tumor microenvironment and activated T cells by adenosine A_2A receptor combined with costimulation of CpG and IL-12 released by DCs for Th1 differentiation, which resulted in IFN-γ production and enhanced ICB therapy

[134]

CRC (MC38); Lewis lung cancer (LLC1); breast cancer (4T1)

Oxaliplatin; αPD-1 mAb

Peptidoglycan

Bifidobacterium bifidum

TLR2

Highly levels of peptidoglycan expressed by Bifidobacterim bifidum can act on the TLR2 receptor to stimulate IFN-γ secretion and improve antitumor therapy by αPD-1 mAb or oxaliplatin

[127]

CRC (AOM-DSS)

αCTLA-4 mAb

Lysates

Lactobacillus acidophilus

Lysates of L. acidophilus decreased Treg and M2 cell levels and increased the proportion of memory CD8⁺ T cells in tumor-draining lymph nodes and mesenteric lymph nodes, thus improving αCTLA-4 mAb efficacy

[147]

Sarcoma (MCA-205); RET melanoma; CRC (CT26/MC38)

αCTLA-4 mAb

Capsular polysaccharide

Bacteroides thetaiotaomicron; Bacteroides fragilis

The capsular polysaccharides of Bacteroides thetaiotaomicron and Bacteroides fragilis induce the maturation of lamina propria DCs, which combined with the Th1 immune response induced by IL-12 secretion and promoted the antitumor effect of αCTLA-4 mAb

[71]

CRC (CT26)

αPD-1 mAb

Glycerophospholipid

Prevotell; Akkermansia

Changes in gut microbiota composition lead to changes in glycerophospholipid metabolism, which affect IFN-γ and IL-2 expression in the tumor microenvironment, resulting in different therapeutic effects of αPD-1 mAb

[148]

CRC (MC38); lymphoma (EG7)

Oxaliplatin

Butyrate

ID2

Butyrate could improve the expression of ID2 by inhibiting HDACs, which promoted IL12R production, and boosted the efficacy of antitumor therapy after stimulation with IL-12 from DCs

[133]