An Orally Available Telomeric G-Quadruplex Ligand Induces Telomere Crisis and Dual DNA/RNA-Sensing Innate Immunity for Cancer Therapy

Telomere crisis is a potent intrinsic barrier against unlimited cancer cell proliferation, offering a promising anticancer strategy. While recent work has implicated both the cGAS-STING DNA-sensing and the TERRA-ZBP1 RNA-sensing pathways, revealing new therapeutic opportunities. Here, we report <b>CA11</b>, an orally bioavailable quinazoline derivative, discovered via a G-quadruplex (G4)-focused screening platform. We demonstrate that pharmacological stabilization of telomeric G4s by <b>CA11</b> provokes a telomere crisis-like phenotype. Mechanistically, these events are associated with the coordinated activation of dual DNA/RNA-sensing innate immune pathways. This dual activation is linked to a potent innate immune response and autophagy, culminating in broad antiproliferative effects across diverse cancer cell lines. <i>In vivo</i>, oral administration of <b>CA11</b> suppresses tumor growth by enhancing innate immunity, and is well tolerated systemically. Our findings establish <b>CA11</b> as the first-in-class and orally activated telomeric G4 ligand that pharmacologically induces telomere crisis for cancer therapy.