Teniposide facilitates macrophage phagocytosis by targeting the CD47-SIRPα axis and the candidate protein TRIM54 in lung cancer.

The precise inhibition of CD47-SIRPα interaction to promote macrophage phagocytosis and thereby mobilize the immune microenvironment is an essential strategy in lung cancer immunotherapy. Herein, we explored the role of Teniposide (Ten/VM-26) in the CD47-SIRPα interactions and macrophage phagocytosis, with insights into the target and molecular mechanism. Ten/VM-26 demonstrated not only chemotherapeutic but also immunostimulatory effects in lung cancer models. Macrophage depletion attenuated the immune activation induced by Ten, which was associated with enhanced phagocytosis, cGAS-STING signaling, and M1 polarization of macrophages. Our data indicated that Ten suppressed CD47 and thereby dampened the interaction between CD47 and SIRPα, which are highly expressed in lung cancer cells and macrophages respectively. Conversely, CD47 supplementation impaired Ten-driven phagocytosis and M1 polarization of macrophages. Further data suggested that Ten bound to TRIM54, which may be involved in CD47 ubiquitination and degradation. To summarize, our findings suggest that Ten down-regulates CD47 through its binding to both CD47 and TRIM54, thereby disrupting the CD47-SIRPα interaction, enhancing macrophage phagocytosis, cGAS-STING activation, and promoting M1 polarization, supporting the potential of targeting CD47 for lung cancer immunotherapy.