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 CA11, an orally bioavailable quinazoline derivative, discovered via a G-quadruplex (G4)-focused screening platform. We demonstrate that pharmacological stabilization of telomeric G4s by CA11 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. In vivo, oral administration of CA11 suppresses tumor growth by enhancing innate immunity, and is well tolerated systemically. Our findings establish CA11 as the first-in-class and orally activated telomeric G4 ligand that pharmacologically induces telomere crisis for cancer therapy.