Microbe-associated molecular patterns, microbial metabolites, and their effect on antitumor activity of cellular therapy
| Microbial metabolites . | Antitumor effect on cellular therapies . | Reference . |
|---|---|---|
| Nongenetically modified cellular therapy | ||
| Cyclic dinucleotide | Activates the stimulator of interferon gene pathway in T cells and NK cells, inhibiting the proliferation of T cells81 but augmenting the antitumor function of T cells82 and NK cells83 | 81-83 |
| SCFAs | Pentanoate and butyrate treatments increase HDAC class I enzyme inhibition and mTOR activity in CTLs, enabling stronger antitumor function through enhanced CD25, TNF-α, and IFN-γ production | 84 |
| Butyrate increases the production of IFN-γ and granzyme B in CTLs | 85 | |
| SCFA receptor GPR109A on T cells increases T-cell activation and alloreactivity by enhancing mitochondrial oxidative phosphorylation while reducing T-cell apoptosis | 86 | |
| Butyrate supports liver-resident NK cells via IL18/IL-18 receptor signaling | 87 | |
| MTCs | Indole-3-propionic acid enhances H3K27ac at the Tcf7 superenhancer, enhances T-cell stemness, progenitor-exhausted CD8+ T-cell differentiation, and antitumor function | 88 |
| Secondary BAs | Microbial BAs attenuate FXR activation, reduce the proliferation of human T cells, and are associated with longer OS in allo-HCT | 89 |
| Protect IECs and maintain the GVL effect | 90 | |
| UA | It improves the persistence and effector functions of CTLs via ERK1/2 signaling | 91 |
| Riboflavin | Riboflavin and HMBPP improve MAIT and Vδ2+ T-cell activation and cytotoxicity | 29 |
| 4-HMBPP | ||
| Genetically modified cellular therapy | ||
| LPS | LPS administration increases adoptively transferred TCR-Ts and enhances their IFN-γ production and antitumor function via Toll-like receptor 4 signaling | 92 |
| SCFAs | Pentanoate and butyrate treatment boosts CD25, TNF-α, and IFN-γ in CAR T cells, enhancing their antitumor function | 84 |
| MTCs | Indole-3-lactic acid enhances the binding of H3K27ac in the enhancer regions of IL12a,93 which can potentiate the cytotoxicity of CAR T cells94 and CAR NK cells95 | 93-95 |
| PAs | Spermidine enhances CAR T-cell proliferation, elevates memory phenotype, and amplifies cytotoxicity in vitro | 96 |
| UA | Enhances CAR T-cell differentiation into TSCM and TCM, and bolsters cytotoxicity through Pink1-dependent mitophagy and the Wnt pathway | 97 |
| It improves the persistence and effector functions of CAR T cells via ERK1/2 signaling | 91 | |
| Inosine | It induces CAR T-cell epigenetic reprogramming and improves CAR T-cell stemness and cytotoxicity | 98 |
| Microbial metabolites . | Antitumor effect on cellular therapies . | Reference . |
|---|---|---|
| Nongenetically modified cellular therapy | ||
| Cyclic dinucleotide | Activates the stimulator of interferon gene pathway in T cells and NK cells, inhibiting the proliferation of T cells81 but augmenting the antitumor function of T cells82 and NK cells83 | 81-83 |
| SCFAs | Pentanoate and butyrate treatments increase HDAC class I enzyme inhibition and mTOR activity in CTLs, enabling stronger antitumor function through enhanced CD25, TNF-α, and IFN-γ production | 84 |
| Butyrate increases the production of IFN-γ and granzyme B in CTLs | 85 | |
| SCFA receptor GPR109A on T cells increases T-cell activation and alloreactivity by enhancing mitochondrial oxidative phosphorylation while reducing T-cell apoptosis | 86 | |
| Butyrate supports liver-resident NK cells via IL18/IL-18 receptor signaling | 87 | |
| MTCs | Indole-3-propionic acid enhances H3K27ac at the Tcf7 superenhancer, enhances T-cell stemness, progenitor-exhausted CD8+ T-cell differentiation, and antitumor function | 88 |
| Secondary BAs | Microbial BAs attenuate FXR activation, reduce the proliferation of human T cells, and are associated with longer OS in allo-HCT | 89 |
| Protect IECs and maintain the GVL effect | 90 | |
| UA | It improves the persistence and effector functions of CTLs via ERK1/2 signaling | 91 |
| Riboflavin | Riboflavin and HMBPP improve MAIT and Vδ2+ T-cell activation and cytotoxicity | 29 |
| 4-HMBPP | ||
| Genetically modified cellular therapy | ||
| LPS | LPS administration increases adoptively transferred TCR-Ts and enhances their IFN-γ production and antitumor function via Toll-like receptor 4 signaling | 92 |
| SCFAs | Pentanoate and butyrate treatment boosts CD25, TNF-α, and IFN-γ in CAR T cells, enhancing their antitumor function | 84 |
| MTCs | Indole-3-lactic acid enhances the binding of H3K27ac in the enhancer regions of IL12a,93 which can potentiate the cytotoxicity of CAR T cells94 and CAR NK cells95 | 93-95 |
| PAs | Spermidine enhances CAR T-cell proliferation, elevates memory phenotype, and amplifies cytotoxicity in vitro | 96 |
| UA | Enhances CAR T-cell differentiation into TSCM and TCM, and bolsters cytotoxicity through Pink1-dependent mitophagy and the Wnt pathway | 97 |
| It improves the persistence and effector functions of CAR T cells via ERK1/2 signaling | 91 | |
| Inosine | It induces CAR T-cell epigenetic reprogramming and improves CAR T-cell stemness and cytotoxicity | 98 |
ERK, extracellular signal–regulated kinase; FXR, farnesoid X receptor; HDAC, histone deacetylase; IFN-γ, interferon gamma; MAIT, mucosal-associated invariant T cells; TCM, central memory T cells; TNF-α, tumor necrosis factor α; TSCM, memory stem T cells.