Fangchinoline Activates cGAS-STING to Promote Antitumor Immunity without Pathological Inflammation.

Effective cancer immunotherapy requires strengthening tumor-directed immunity while avoiding pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we identified fangchinoline (Fan) as a dual immunomodulator that activated antitumor immune responses and restrained hyperinflammation. Fan induced robust type I interferon production across multiple human and murine cell types and in mice, and these responses were largely abolished by genetic deletion of cGAS or STING. Mechanistically, Fan directly bound and sensitized human cGAS and enhanced 2',3'-cGAMP synthesis, including detectable activity in the absence of exogenous DNA, and this effect required an intact catalytic center. In vivo, Fan suppressed tumor growth in B16F10 melanoma and Pan02 pancreatic cancer models, increased intratumoral immune activation, and improved the efficacy of PD-1 blockade. Single-cell and multi-omics analyses further revealed coordinated transcriptional, chromatin-accessibility, and intercellular communication changes that supported enhanced CD8⁺ T cell effector programs within the tumor microenvironment. In parallel, Fan attenuated LPS-driven inflammatory responses in macrophages, reversed LPS-associated transcriptional and chromatin-opening programs, and improved survival in an endotoxemia model. Together, these findings established Fan as a cGAS-targeting immunomodulator that coupled antitumor immunity with control of inflammatory toxicity, providing a potential strategy to broaden the therapeutic window of immune activation.