STING suppresses bone cancer pain via immune and neuronal modulation

Abstract

Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

“…Chemokines and their receptors-associated neuroinflammation is essential for OIH generation ( Yang et al, 2016 ; Zhu et al, 2017 ). Wang et al (2020a) confirmed that remifentanil infusion causes mechanical allodynia and thermal hyperalgesia, along with the spinal increase in the cleavage of caspase-6, the release of CCL21 in neurons and the expression of CXCR3 in microglia. Spinal inhibition of caspase-6 activation ameliorates OIH behavior and spinal CCL21/CXCR3 accumulation.…”

“…Cancer pain is also an important category of chronic pain and have the distinctive characteristic of both neuropathic pain and inflammatory pain processing ( Wang K. et al, 2020 ; Wang K. et al, 2021 ). Mounting evidence reveal that the expression of NLRP3 inflammasome, including NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1, were significantly increased in a time-dependent manner in bone cancer pain ( Chen et al, 2019 ).…”

Type I interferon-mediated tumor immunity and its role in immunotherapy

“…DMXAA, also known as ASA404 or vadimezan, is a strong STING agonist without significant local or systemic toxicity and was shown to have anti-tumor immunity in mouse models. In a previous study, DMXAA showed anti-angiogenic effects [ 83 ], and recent reports found that STING activation by DMXAA reduced bone cancer pain and local tumor burden [ 84 ], and promoted CAR T cell trafficking and persistence in breast cancer [ 85 ]. Although it had various beneficial effects in preclinical models, DMXAA was ineffective when combined with platinum-based chemotherapy in a phase 3 efficacy trial in human patients with advanced non-small-cell lung cancer (NSCLC) [ 86 , 87 ].…”

The cGAS-STING Pathway Affects Vertebral Bone but Does Not Promote Intervertebral Disc Cell Senescence or Degeneration

“…Previous studies have correlated STING expression with elevated osteoblastic activity in a model of DNA damage-induced inflammation (DNaseII -/- , IFNR -/- ), but IL-1β, IL-6, TNF-α stimulate osteoclast differentiation, which may also explain the compromised bone quality in N153S mice ( 26 , 58 , 59 ). Of note, recent work demonstrated STING induction through DMXAA treatment in mice attenuates cancer-induced osteoclast differentiation in the femur through type I interferon signaling and that STING induction inhibited bone fracture-induced pain by suppressing nociceptor excitability ( 60 ). These results show an opposite effect of STING activation on bone cells in the femur than that observed in the vertebrae in the present study; one possible explanation for such is the impact of proinflammatory signaling in the absence of direct insult to the tissue as opposed to in the context of injury or a diseased tissue microenvironment.…”