PRMT7 restricts CD8 + T cells expansion via the NF-κB pathway
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New therapeutics are needed to enhance cytotoxic T lymphocyte (CTL) expansion and effector function for effective tumor control. Here, we show that T cell specific deletion of Prmt7 using CD4-Cre mice increases CD8 + effector differentiation, cytokine secretion, cytolytic activity, and anti-tumor responses. Prmt7 deficiency transcriptionally reprogrammed CD8 + T cells by activating the NF-κB pathway, boosting proliferation, and elevating effector molecules such as CD25, CD69, and IFNγ. Mechanistically, PRMT7 associated with RelA and restricted its nuclear translocation. To enable therapeutic translation, we developed a PRMT7-targeting PROTAC degrader (MS54). MS54-treated CTLs exhibited NF-κB pathway activation similar to Prmt7-deficient CTLs. Adoptive transfer of MS54-treated OT-I CTLs significantly improved tumor control in a syngeneic melanoma model. In human CTLs, MS54 enhanced proliferation, activation markers (CD69, CD137), IFNγ production, and cytotoxicity toward melanoma. Together, these findings identify PRMT7 as a negative regulator of CD8 + T cell immunity and highlight MS54 as a promising strategy to improve adoptive T cell therapy.
