Table 2 m6A-mediated regulation of diverse immune cells in the tumor microenvironment.
Regulation of lymphoid cell functions | ||||||
|---|---|---|---|---|---|---|
Cell types | Regulators | m6A substrate | Cancer types | Mechanism | Phenotype | Reference(PMID) |
T cells | METTL3 METTL14 | Stat1, Irf1 | CRC | Depletion of METTL3 or METTL14 inhibit the m6A level but stabilizes Stat1 and Irf1 mRNAs, hence activating IFN-γ-Stat1-Irf1 signaling. | Depletion of METTL3 and METTL14 enhances response to anti-PD-1 treatment in pMMR-MSI-L CRC and melanoma; METTL3 or METTL14 deficient tumors increased cytotoxic tumor-infiltrating CD8+ T cells and elevated secretion of IFN-γ, Cxcl9, and Cxcl10 in tumor microenvironment in vivo. | 32964498 |
T cells | ALKBH5 | Mct4, Slc16a3 | CRC | ALKBH5 regulated Mct4 expression by decreasing its m6A levels and RNA stability. | Suppressing Tregs and myeloid-derived suppressor cell accumulations; ALKBH5 knockout in tumor cells enhances efficacy of immunotherapy and increased mouse survival. | 32747553 |
T cells | YTHDF1 | unknown | GC | Depletion of YTHDF1 promotes IFN-γ receptor 1 expression and enhances IFN-γ response, promoting expression of major histocompatibility complex class I (MHC I). | Promotes self-presentation of the immunogenic tumor cells to stimulate a strong cytotoxic T lymphocytes responses. | 36484103 |
T cells | YTHDF1 | PD-L1, VISTA | CRC | YTHDF1 regulates PD-L1 and VISTA expression in an m6A dependent manner. | YTHDF1 depletion inhibited tumor growth by enhancing the infiltration of CD8+ T cells and synergized with PD-1 blockade for cancer treatment. | 35803704 |
T cells and NK cell | IGF2BP1 | c-MYC, KRAS | HCC | CuB (Cucurbitacine B) promoted IGF2BP1-dependent target mRNA instability. | Induces tumor cell apoptosis, and recruits various immune cells (CD4+ and CD8+ T cells, CD56+ NK cells, and F4/80+ macrophages). | 36032766 |
NK cells | METTL3 | SHP2 | CRC | METLL3 depletion attenuates the m6A modification and stability of SHP-2, thus activating AKT and MAPK signaling pathway. | Inhibits NK cell infiltration and function, leading to tumor growth and shortened survival in mice. | 34535671 |
Regulation of myeloid cell functions | ||||||
Cell types | Regulators | m6A substrate | Cancer types | Mechanism | Phenotype | Reference |
TIMs (including TAMs, TANs, MDSCs) | METTL3 | Jak1 | CRC | METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. | METTL3/JAK1/STAT3 axis strengthens immunesuppressive functions of myeloid cells. | 35320754 |
MDSCs | METTL3 | BHLHE41 | CRC | METTL3 promoted BHLHE41 expression in an m6A-dependent manner. | METLL3 enhances MDSC migration in CRC. | 35700773 |
MDSCs | YTHDF1 | p65 | CRC | YTHDF1 activates CXCL1-CXCR2 axis by promoting m6A-p65 translation. | Promoting MDSC migration and antagonizing functional CD8+ T cells it the TIME. | 36717220 |
Macrophages | METTL14 | Ebi3 | CRC | Loss of METTL14 in C1q+ macrophages promote the accumulation of Ebi3 mRNA in an m6A dependent manner. | METTL14 deficiency in macrophages impairs the antitumor response and CD8+ T cell dysfunction, contributing to tumor growth. | 34019807 |
Macrophages and MDSCs | ALKBH5 | PD-L1 | ICC | Loss of ALKBH5 enhances the m6A modification on the 3’ UTR of PD-L1 mRNA accelerating its degradation in a YTHDF2-dependent manner. | ALKBH5 promotes the expression of PD-L1 on monocyte/macrophage cells decreasing the infiltration of MDSC-like cells to the TIME. | 34301762 |
DCs | YTHDF1 | CTSA, CTSB, CTSD, CTSH | CRC | Transcripts encoding lysosomal proteases are marked by m6A and recognized by YTHDF1, thus increasing the translation of lysosomal cathepsins in dendritic cells. | YTHDF1 depletion inhibits cathepsins to enhance cross-presentation of wild-type dendritic cells. Enhanced antigen-specific CD8+ T cell anti-tumor response and PD-L1 blockade efficacy. | 30728504 |
DCs | YTHDF1 | IFN-γ1 | GC | Depletion of YTHDF1 amplifies DC-mediated anti-tumor immune response including CD4+ and CD8+ T cells infiltration with increased IFN-γ secretion. | Promoting GC by inducing cell proliferation and repression of DC-mediated antitumor immune response including CD4+ and CD8+ T cells infiltration with increased IFN-γ secretion | 35193930 |
