IMMUNOLOGY2025™ Conference Recordings-The cGAS-STING pathway as a therapeutic target

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Video Summary

The speaker introduced a major theme in innate immunity: cells detect foreign nucleic acids to trigger type I interferons and other defenses. They explained that unlike ancient sequence-specific systems such as CRISPR, vertebrate sensors like cGAS, RIG-I, and MDA5 detect structural features of nucleic acids, which makes self-recognition a risk. The lab studies how these pathways are restrained by enzymes such as TREX1, ADAR1, and SKIV2L, since failure of these safeguards causes inflammatory disease.<br /><br />The talk focused on cGAS and its product, cGAMP, a small second messenger that activates STING. The lab identified ABCC1 (MRP1) as the first known cGAMP exporter. Using macrophages, pharmacologic inhibition, CRISPR knockouts, transporter vesicle assays, and structural data, they showed that ABCC1 directly and ATP-dependently transports cGAMP. Loss of ABCC1 increases intracellular STING signaling and worsens TREX1-deficient autoimmune disease.<br /><br />The speaker then extended this to cancer. In tumor models, cGAMP made by tumor cells can exit via ABCC1 and activate STING in host immune cells, shaping the tumor microenvironment and slowing tumor growth. New unpublished data showed that ABCC1 loss blocks cGAMP export from tumor cells, alters myeloid populations in tumors, and accelerates tumor growth, suggesting ABCC1 may be important for anti-tumor immunity, not just drug resistance.

Keywords

innate immunity

cGAS-STING pathway

cGAMP export

ABCC1/MRP1

TREX1 deficiency

autoimmune inflammation

tumor microenvironment