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

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.

• NN
  National Natural Science Foundation of China

  Awards: 82173301, 82121002
• OD
  Organization Department of the Central Committee of the Communist Party of China
• NP
  National Program for Support of Top-notch Young Professionals