International Immunopharmacology · Oct 28, 2026

Rapamycin attenuates bone cancer pain and tumor progression associated with reduced NE/NETosis-related molecular signatures in a mouse model

By Li W, Wang X, Wang L et al.

Bone cancer pain (BCP) is a refractory condition associated with tumor metastasis for which effective treatment options remain limited. Although NETosis-related inflammatory processes and neutrophil elastase (NE) have been implicated in pathological pain, their association with BCP remains insufficiently characterized. Here, we investigated NETosis-related molecular alterations in a BCP mouse model and evaluated the analgesic and antitumor effects of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor with immunomodulatory properties. The BCP model was established by injecting Lewis lung carcinoma cells into the femur, resulting in progressive mechanical allodynia, heat hyperalgesia, and spontaneous pain. Spinal transcriptomic analysis revealed enrichment of genes associated with NETosis-related processes, with upregulated expression of Elane and Mpo mRNA. Exploratory molecular docking was performed to visualize a possible interaction pattern between rapamycin and NE. In vivo, rapamycin (1.5-5 mg/kg, i.p.) produced dose-related attenuation of pain-related behaviors. The 5 mg/kg dose showed the greatest behavioral improvement and was selected for subsequent analyses. Western blotting and immunofluorescence demonstrated that rapamycin treatment was associated with reduced levels of NETosis-associated markers, including NE, MPO, and citrullinated histone H3, in the spinal cord. Rapamycin treatment was also associated with reduced local tumor growth. Collectively, these findings suggest that NE/NETosis-related molecular alterations may represent a relevant feature of BCP pathophysiology. Rapamycin attenuated pain-related behaviors and was associated with reduced local tumor burden and lower levels of NE/NETosis-related molecular markers in this mouse model, suggesting that these molecular alterations may accompany the observed beneficial effects.

doi.org/10.1016/j.intimp.2026.117610 PubMed 42950646 Interventions