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STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity

Jianwen Pei1, Yibo Zhang1, Qinhong Luo1

  • 1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.

Cancer Letters
|February 22, 2019
PubMed

Insights

STAT3 inhibition enhances the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway signaling. This combination therapy promotes antitumor immunity by modulating immune cells in the tumor microenvironment.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for innate immunity and cancer treatment.
  • Its therapeutic utility is complex due to dual roles in tumor development and immunity.
  • Interleukin-6/STAT3 (Signal Transducer and Activator of Transcription 3) pathway activation can dampen STING-induced antitumor responses.

Purpose of the Study:

  • To investigate the effect of STAT3 inhibition on STING pathway activation.
  • To explore the therapeutic potential of combining STAT3 inhibitors with STING agonists in cancer immunotherapy.

Main Methods:

  • Utilized a STING agonist (c-diAM(PS)2) and a STAT3 inhibitor.
  • Assessed STING signaling intensity and duration.
  • Analyzed immune cell populations (CD8+ T cells, Tregs, MDSCs) in the tumor microenvironment of syngeneic mouse models.

Main Results:

  • STAT3 inhibition significantly amplified STING signaling, dependent on STING rather than cGAS.
  • This sensitization involved upregulating positive and downregulating negative modulators of the STING pathway.
  • Combination treatment markedly regressed tumor growth by enhancing CD8+ T cells and reducing Tregs and MDSCs.

Conclusions:

  • STAT3 inhibition potentiates STING pathway signaling and antitumor immunity.
  • Combining STAT3 inhibitors with STING agonists offers a promising strategy for cancer immunotherapy.
Keywords:
ImmunityImmunotherapySTAT3Tumor microenvironmentcGAS-STING

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