Table 2.

Reports on microbial metabolites that affect immunotherapy

Tumor type	Immunotherapy treatment	Microbial metabolites	Metabolic bacterial taxa	Target	Overview of mechanism	References
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 (BRAFV600E/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	A2A receptor	Inosine produced by the gut microbiota can translocate to the tumor microenvironment and activated T cells by adenosine A2A 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]

TAM tumor associated macrophage, IL-2/12/22 interleukin-2/12/22