p300/CBP-Driven Acetylation Stabilizes PARP7 to Reinforce Negative Feedback on IFN-I Signaling

Li, D.; Liu, Y.; Wang, Y.; Liu, W.; Zhu, S.; Zhang, Y.; Wang, L.; Zhou, X.; Ding, W.; Dang, Y.; Wu, J.

doi:10.64898/2026.01.28.702217

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bioRxiv · 10.64898/2026.01.28.702217

p300/CBP-Driven Acetylation Stabilizes PARP7 to Reinforce Negative Feedback on IFN-I Signaling

Li, D.·Liu, Y.·Wang, Y.·Liu, W.·Zhu, S.·Zhang, Y.·Wang, L.·Zhou, X.·Ding, W.·Dang, Y.·Wu, J.

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Abstract

Immune suppression within the tumor microenvironment (TME) remains a major barrier to effective immunotherapy, yet the molecular mechanisms that constrain type I interferon (IFN-I) signaling in tumor cells are incompletely understood. PARP7 (also known as TIPARP), a mono-ADP-ribosyltransferase, has been reported to suppress IFN-I signaling by modifying TBK1. Here, we identify PARP7 as a previously unrecognized acetylation substrate of the histone acetyltransferases p300 and CBP. We show that p300/CBP-mediated acetylation of PARP7 at lysine 32 markedly enhances its stability, thereby reinforcing repression of the TBK1-IRF3-STAT1 axis and suppressing IFN-{beta}-induced expression of interferon-stimulated genes, including CXCL10. Beyond their established function as transcriptional co-activators that support tumor cell proliferation, our findings uncover a direct role for p300/CBP in shaping innate antitumor immunity. Pharmacological inhibition of p300/CBP catalytic activity by A-485 abolishes PARP7 acetylation, accelerates its proteasomal turnover, and restores IFN-I signaling. In immunocompetent tumor models, this is accompanied by enhanced CD8+ T-cell infiltration and effector function. Together, these findings define a p300/CBP-PARP7 regulatory axis, uncover a non-canonical role for p300/CBP in innate immune suppression, and nominate this pathway as a tractable target for restoring antitumor immunity.

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Li, D., Liu, Y., Wang, Y., Liu, W., Zhu, S., Zhang, Y., Wang, L., Zhou, X., Ding, W., Dang, Y., Wu, J.. 2026-01-30. p300/CBP-Driven Acetylation Stabilizes PARP7 to Reinforce Negative Feedback on IFN-I Signaling. https://doi.org/10.64898/2026.01.28.702217

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