Microbiota-reprogrammed phosphatidylcholine inactivates cytotoxic CD8 T cells through UFMylation via exosomal SerpinB9 in multiple myeloma

Gut microbiome influences tumorigenesis and tumor progression through regulating the tumor microenvironment (TME) and modifying blood metabolites. However, the mechanisms by which gut microbiome and blood metabolites regulate the TME in multiple myeloma (MM) remain unclear. By employing16S rRNA gene sequencing coupled with metagenomics and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, we find that Lachnospiraceae are high and phosphatidylcholine (PC) are low in MM patients. We further show that Lachnospiraceae inhibits PC production from MM cells and enhances cytotoxic CD8 T cell function. Mechanistically, PC promotes Sb9 mRNA maturation in MM cells by LIN28A/B via lysophosphatidic acid, thus enhances exosamal Sb9 production. Exosamal Sb9 then reduces GZMB expression by suppressing tumor protein p53 (TP53) UFMylation via the competitive binding of TP53 with the ubiquitin-fold modifier conjugating enzyme 1 in CD8 T cells. We thus show that Lachnospiraceae and PC may be potential therapeutic targets for MM treatment.