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

2026 · doi:10.64898/2026.04.25.720790
preprint OA: closed
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The study investigated how PRMT7 regulates CD8+ cytotoxic T lymphocyte (CTL) expansion and effector function, using T cell–specific Prmt7 deletion in CD4-Cre mice and complementary mechanistic experiments. Prmt7 deficiency increased CD8+ effector differentiation, cytokine secretion, cytolytic activity, and anti-tumor responses, and was linked to transcriptional reprogramming through NF-κB pathway activation with greater proliferation and higher expression of markers including CD25, CD69, and IFNγ; a stated mechanistic limitation is that the work focuses on the NF-κB/RelA axis without detailing broader pathway coverage beyond the reported mechanism. The authors then developed a PRMT7-targeting PROTAC degrader (MS54) that produced similar NF-κB activation phenotypes, and showed improved tumor control in a syngeneic melanoma model with adoptive transfer of MS54-treated OT-I CTLs, along with increased proliferation, activation markers, IFNγ, and melanoma cytotoxicity in human CTLs. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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.
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Abstract 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. Competing Interest Statement The authors have declared no competing interest.

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