Understand the anti-cancer STING pathway and harness it to treat metastatic cancers
The 2018 Nobel Prize in Medicine honored the discovery of cancer therapy that blocks adaptive immune checkpoints. These therapies are now curing ~20% of previously considered terminally ill melanoma patients because melanomas are immunogeneic tumors heavily infiltrated by immune cells (also known as “hot tumors”). However, they have not been effective in most cancers which are less immunogenic (also known as “cold tumors”).
The innate immune STING (stimulator of interferon genes) pathway is now recognized as a central pathway in anti-cancer immunity because it senses cytosolic double-stranded DNA (dsDNA), a hallmark of cancers due to their frequent erroneous chromosomal segregation. Upon sensing of cytosolic dsDNA, cyclic-GMP-AMP-synthase (cGAS) produces the second messenger 2’3’-cyclic- GMP-AMP (cGAMP) in the cytosol, which binds to and activates its receptor STING. STING activation leads to production of type-I interferons, a potent cytokine that then activates downstream immune responses aginst cancer.
My lab has identified the role of cGAMP as an immunotransmitter that alerts our immune system of cancer. We have also uncovered regulation mechanisms of extracellular cGAMP signaling including how it activates STING and its degradation enzyme and transporters. We identified ENPP1, the dominant hydrolase of cGAMP, as an innate immune checkpoint and important target for cancer immunotherapy. We developed promising drug candidates that one day may benefit patients with cold tumors that previously do not respond to adaptive immune checkpoint blockers.
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- Prof Yimon AYE