STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation

Cell Rep. 2016 Sep 13;16(11):2914-2927. doi: 10.1016/j.celrep.2016.08.035.


Tumor-associated macrophages play critical roles during tumor progression by promoting angiogenesis, cancer cell proliferation, invasion, and metastasis. Cysteine cathepsin proteases, produced by macrophages and cancer cells, modulate these processes, but it remains unclear how these typically lysosomal enzymes are regulated and secreted within the tumor microenvironment. Here, we identify a STAT3 and STAT6 synergy that potently upregulates cathepsin secretion by macrophages via engagement of an unfolded protein response (UPR) pathway. Whole-genome expression analyses revealed that the TH2 cytokine interleukin (IL)-4 synergizes with IL-6 or IL-10 to activate UPR via STAT6 and STAT3. Pharmacological inhibition of the UPR sensor IRE1α blocks cathepsin secretion and blunts macrophage-mediated cancer cell invasion. Similarly, genetic deletion of STAT3 and STAT6 signaling components impairs tumor development and invasion in vivo. Together, these findings demonstrate that cytokine-activated STAT3 and STAT6 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsin-dependent manner.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cathepsins / genetics
  • Cathepsins / metabolism*
  • Cytokines / pharmacology
  • Endoribonucleases / metabolism
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Macrophages / metabolism*
  • Mice
  • Neoplasm Invasiveness
  • Phenotype
  • Protein Serine-Threonine Kinases / metabolism
  • STAT3 Transcription Factor / metabolism*
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction
  • Th2 Cells / drug effects
  • Th2 Cells / metabolism
  • Transcription, Genetic / drug effects
  • Unfolded Protein Response / drug effects


  • Cytokines
  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Cathepsins