Discovery of synthetic TBK1 activator inducing type I interferon-mediated antiviral and antitumor immunity.

Type I interferons (IFNs) are central regulators of innate immunity, coordinating antiviral defense and tumor immune surveillance. However, therapeutic strategies that selectively engage IFN signaling while maintaining controlled outputs remain limited. Here, we identify a synthetic small molecule that induces robust type I IFN responses. Mechanistic analyses demonstrate that the compound directly engages TANK-binding kinase 1 (TBK1), leading to IRF3 phosphorylation and selective activation of IFN-stimulated gene programs. In contrast to nucleotide-based innate immune agonists that signal through upstream pattern-recognition receptors, this molecule activates TBK1 through direct chemical engagement. TBK1 activation confers host-directed antiviral activity against coronaviruses, including SARS-CoV-2, through induction of interferon-stimulated genes. The compound also modulates the tumor immune microenvironment toward an immunologically active state, characterized by enhanced antigen presentation and increased infiltration of cytotoxic T cells, resulting in augmented antitumor immune responses in vivo. These immunomodulatory effects reflect coordinated activation of innate and adaptive immune pathways downstream of IFN signaling. Chemical activation of the TBK1-IRF3-IFN axis underscores the druggability of this signaling pathway for selective innate immune modulation in viral infection and cancer.