STING-IL-6 signaling in sensory neurons drives cisplatin-induced neuropathic pain

Cisplatin-induced neuropathic pain (CINP) is a frequent and debilitating adverse effect of chemotherapy that can persist long after treatment cessation and remains poorly controlled by current therapies. Identifying the mechanisms that drive CINP is therefore critical for developing effective interventions. Cisplatin has been reported to cause mitochondrial dysfunction and promote the release of mitochondrial DNA (mtDNA) into the cytosol, putatively through BCL2 associated X protein (BAX) pores, thereby activating stimulator of interferon genes (STING), a cytosolic double stranded DNA sensor. We have previously shown that activating STING signaling in nociceptors can induce pain. Here, we tested whether cisplatin engages STING signaling in nociceptors and promotes neuropathic pain. In a mouse model of CINP induced by repeated cisplatin administration (2 mg per kg per day, intraperitoneally, for three consecutive days), we observed increased BAX mRNA expression and cytosolic double stranded DNA in dorsal root ganglion (DRG) tissues containing nociceptors. Genetic ablation of STING signaling, either globally (Sting^gt/gt) or selectively in nociceptors, significantly attenuated CINP. Mechanistically, STING activation in nociceptors promoted neuropathic pain through induction of interleukin-6 (IL-6), independently of type I interferon pathways. Pharmacological inhibition of STING reduced CINP development and IL-6 upregulation and prevented epidermal sensory fiber loss. Together, these findings identify a previously unrecognized pronociceptive role for STING signaling in nociceptors during CINP and support peripheral STING inhibition as a therapeutic strategy.