Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

Xiuting Liu, Graham D. Hogg, Chong Zuo, Nicholas C. Borcherding, John M. Baer, Varintra E. Lander, Liang I. Kang, Brett L. Knolhoff, Faiz Ahmad, Robin E. Osterhout, Anna V. Galkin, Jean Marie Bruey, Laura L. Carter, Cedric Mpoy, Kiran R. Vij, Ryan C. Fields, Julie K. Schwarz, Haeseong Park, Vineet Gupta, David G. DeNardo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

Original languageEnglish
Pages (from-to)1073-1090.e12
JournalCancer Cell
Issue number6
StatePublished - Jun 12 2023


  • CD11b
  • NF-κB
  • immunotherapy
  • pancreatic cancer
  • tumor-associated macrophages


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