Thecrosstalk between immune cells and tumor cells within tumor microenvironmentcrucially determines the fate of tumor progression and metastasis. Cancerimmunotherapy has brought unprecedented success in clinical benefits formultiple types of cancer by reinvigorating the functions of tumor-infiltratinglymphocytes. However, the majority of patients do not benefit fromimmunotherapies because of the accumulation of immunosuppressivetumor-infiltrating myeloid cells (TIMs). Emerging evidence indicates that TIMsare critical players in suppressing T cell function and promoting the tumorprogression after being converted into potent immunosuppressive cells.Recently, a growing number of evidence has demonstrated that RNAN6-methyladenosine (m6A) modification plays critical roles in regulating tumorprogression and tumor immunity. However, the precise regulation mode of m6Amodification in controlling TIMs function is still poorly understood.
OnMarch 22nd, Prof. WANG Qingqing, and Prof. LAI Lihua from the Institute of Immunology cooperatedwith Prof. DING Kefeng from the Second Affiliated Hospital, Zhejiang UniversitySchool of Medicine published an article entitled Lactylation-drivenMETTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltratingmyeloid cells in the journal MolecularCell. This study discovered that lactate in tumor microenvironment is a keyfactor for inducing the expression and function of RNA methyltransferasemethyltransferase-like 3 (METTL3). METTL3-mediated m6A modification potentlyenhances the immunosuppressive functions of TIMs to promote tumor immuneescape.
Inthis study, it is found that increased expression of METTL3 in TIMs wascorrelated with the poor prognosis of colon cancer patients and myeloid deficiencyof METTL3 attenuated tumor growth in mice. METTL3-mediated m6A modification onJak1 mRNA in TIMs, m6A-YTHDF1 axis enhanced JAK1 protein translation efficiencyand subsequent phosphorylation of STAT3. Lactate accumulated in tumormicroenvironment potently induced METTL3 upregulation in TIMs via H3K18lactylation. Interestingly, the research team identified two lactylationmodification sites in the zinc finger domain of METTL3, which was essential forMETTL3 to capture target RNA.
Overall,the results emphasize the lactylation-METTL3-JAK1-STAT3 regulatory axispotently induces the immunosuppressive functions of TIMs. The findings in thepresent study led us to expect that METTL3 inhibitor might have the potentialas a novel immunotherapeutic strategy for the intervention of colorectalcancer.
