CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells

J Immunother Cancer. 2022 Jan;10(1):e003459. doi: 10.1136/jitc-2021-003459.


Background: While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive.

Methods: Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer.

Results: We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer.

Conclusion: Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

Keywords: CD4-positive T lymphocytes; adaptive immunity; immunomodulation; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Female
  • Interferon Regulatory Factor-3 / physiology
  • Interleukin-9 / physiology*
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Nucleotides, Cyclic / pharmacology
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / physiology
  • Th1 Cells / cytology
  • Th1 Cells / immunology*


  • Interferon Regulatory Factor-3
  • Interleukin-9
  • Irf3 protein, mouse
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Sting1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases