Targeting Dectin-1/Syk axis alleviates chemotherapy-induced cognitive impairment via STING signaling pathway.

Chemotherapy-induced cognitive impairment (CICI) is a potential long-term side effect during cancer treatment. Dendritic cell-associated C-type lectin-1 (Dectin-1)/spleen tyrosine kinase (Syk) axis is involved in multiple inflammatory diseases. However, the role of Dectin-1/Syk axis in CICI and its possible mechanisms remain unclear. In this study, we revealed that DOX triggered the activation of Dectin-1/Syk axis in the hippocampus of DOX-treated mice and astrocytes. Pharmacological blockade of Dectin-1 rescued DOX-induced cognitive dysfunction, improved synaptic loss, and reduced neuroinflammation. Transcriptomic analysis demonstrated that the inactivation of STING signaling contributed to Dectin-1 blockade-mediated neuroprotection. Furthermore, STING activation diminished the neuroprotective effects of Dectin-1 inhibition in DOX-treated mice. Importantly, Syk was essential for Dectin-1-mediated STING signaling activation and inflammatory responses both in vivo and in vitro. Mechanistically, we verified that DOX could bind to Dectin-1 directly, induce its homodimerization, and subsequently increase the recruitment of Syk. In summary, our findings provided fresh insights into the molecular mechanisms of DOX-induced CICI and highlighted that Dectin-1/Syk axis might be a potential pharmacological target for the treatment of CICI.