Compound 296

Compound 296 is a selective small-molecule inhibitor of three prime repair exonuclease 1 (TREX1), an innate immune checkpoint enzyme. TREX1 typically functions by degrading cytosolic DNA to suppress the activation of the cGAS-STING pathway, a mechanism that many cancers exploit to evade immune detection. By inhibiting TREX1 DNase activity, Compound 296 leads to the accumulation of cytosolic DNA in cancer cells, which triggers robust type I interferon (IFN-I) signaling. This innate immune activation promotes the infiltration of CD8+ T cells into the tumor microenvironment, leading to tumor regression. Developed at the University of Texas Southwestern Medical Center, primarily in Dr. Nan Yan's laboratory, Compound 296 has shown preclinical efficacy in reprogramming immunologically "cold" tumors and synergizing with anti-PD-1 immune checkpoint blockade therapy without significant systemic toxicity.