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. 2025 Mar 10;43(3):503-518.e10.
doi: 10.1016/j.ccell.2025.02.014.

Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy

Affiliations

Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy

Huan Song et al. Cancer Cell. .

Abstract

STING is an important DNA sensing machinery in initiating immune response, yet therapies targeting STING have shown poor outcomes in clinical trials. Here, we reveal that STING signaling induces PD-L1hi tumor monocytes (Tu.Mons) that dominate the resistance against STING agonist therapy. Cell-intrinsic PD-L1, induced by the STING-IRF3-IFN-I axis, is identified as the driving factor for protumoral PD-L1hi Tu.Mons. Notably, TLR2-activated Tu.Mons resist STING-induced upregulation of cell-intrinsic PD-L1 and the associated protumoral functions. Mechanistically, TLR2 stimulation remodels STING signaling by facilitating STING and TRAF6 interaction, which suppresses the IRF3-IFN-I response and enhances NF-κB activation. Moreover, we demonstrate that combining STING agonists with TLR2 agonist pretreatment significantly improves antitumor efficacy in murine syngeneic and humanized models. Our findings uncover a protumoral aspect of STING activation mediated by cell-intrinsic PD-L1 and propose a promising strategy to boost antitumor immunity by fine-tuning STING signaling outputs.

Keywords: STING signaling; TLR2 signaling; cancer; cell-intrinsic PD-L1; tumor monocytes.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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