PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.

Successful cellular immunotherapy for cancer utilising cytotoxic T lymphocytes (CTL) requires efficient expansion while maintaining effector function. Understanding how CTL expansion and function are regulated during the cell preparation process is thus important. Here, we show that T cell-specific deletion of Prmt7 using CD4-Cre increases CD8+ T cell effector differentiation, cytokine secretion, cytolytic activity and anti-tumor responses. Prmt7 deficiency transcriptionally reprograms CD8+ T cells by activating the NF-κB pathway, boosting proliferation, and facilitating the production of effector molecules such as CD25, CD69 and IFNγ. Mechanistically, PRMT7 associates with RelA and restricts RelA nuclear translocation. In vitro, a self-developed PRMT7-targeting PROTAC degrader, MS54, similarly activates the NF-κB pathway as in Prmt7-deficient CTL. In vivo, adoptive cell transfer of MS54-treated OT-I CTLs improves tumor control in a mouse syngeneic melanoma model. In human CTL, MS54 enhances proliferation, activation markers (CD69, CD137) expression, IFNγ production and cytotoxicity toward melanoma. Our findings thus identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a potential strategy to improve adoptive T cell therapy.