Phosphatidylcholine inactivates cytotoxic CD8+ T cells through UFMylation via exosomal SerpinB9 in multiple myeloma

Novel therapeutic targets must be identified to improve the outcomes of patients with multiple myeloma (MM). The gut microbiome influences tumorigenesis and tumor progression through regulating the tumor microenvironment (TME) and modifying blood metabolites. Therefore, targeting the gut microbiome and blood metabolites to modulate the TME is a promising strategy for MM treatment. However, the mechanisms by which the gut microbiome and blood metabolites regulates the TME in MM remain unclear, and this study aimed to investigate the mechanisms. Results of 16S rRNA gene sequencing coupled with metagenomics and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry revealed that Lachnospiraceae and phosphatidylcholine (PC) are critical differentiators between patients with MM and healthy individuals. PC hindered the cytotoxic effect of CD8+ T cells on MM cells via SerpinB9 (Sb9) in vitro and in vivo. Mechanistically, PC promoted Sb9 mRNA maturation and expression in MM cells by LIN28A/B via lysophosphatidic acid (LPA). Moreover, PC inhibited the cytotoxicity of CD8+ T cells on MM cells through reducing granzyme B (GZMB) expression in CD8+ T cells by exosomal Sb9 derived from MM cells via LPA. Furthermore, Sb9 reduced GZMB expression by inhibiting TP53 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. This study provides potential novel targets and strategies for MM treatment.