<p>Cancer-related pain and anxiety significantly negate the quality of life in patients. Oligodendrocyte precursor cells (OPCs) were reported to involve in engulf synapses and remodel neural circuits. This study aimed to elucidate the role of OPCs-mediated phagocytosis of GABAergic synapses in a mouse model of bone cancer pain. Male C3H mice were utilized to establish a model of bone cancer pain. In vivo fiber photometry was used to monitor the activity of GABAergic neurons, and chemogenetic techniques were applied to modulate neuronal excitation. The phagocytosis of GABAergic synapses by OPCs was visualized via immunofluorescence-based 3D reconstruction and immunoelectron microscopy. Interventions targeting lipocalin-2 (LCN2) and its receptor SLC22A17 were carried out with adeno-associated virus (AAV), siRNA, and pharmacological tools. On the 21st postoperative day, mice with bone cancer displayed significant pain and anxiety-like behaviors. Tumor-bearing mice exhibited a compensatory increase in calcium activity among GABAergic neurons within the anterior cingulate cortex (ACC). Compared with sham-operated mice, OPC phagocytosis of GABAergic synapses was higher in the tumor-bearing mice than controls. Concurrently, a pronounced upregulation of LCN2 expression was observed in the tumor group. Administration of LCN2-neutralizing antibodies or AAV-mediated intervention markedly alleviated pain and anxiety-related behaviors in mice with bone cancer. Moreover, the LCN2 receptor SLC22A17 expression was significantly increased. Targeted inhibition of SLC22A17 induced cytoskeletal remodeling and decreased their phagocytic capacity of OPCs. Collectively, LCN2/SLC22A17 signal was involved in OPCs-mediated phagocytosis of GABAergic synapses and contributed to cancer pain and anxiety development.</p> Graphical abstract <p></p>