CSF1R inhibition agents protect against cisplatin ototoxicity and synergize with immunotherapy for Head and Neck Squamous Cell Carcinoma.

Immunotherapy has emerged as a promising therapeutic approach. However, limited research exists on combining cisplatin with CSF1/CSF1R immunotherapy in Head and Neck Squamous Cell Carcinoma. Furthermore, few studies have investigated concurrent immunotherapeutic strategies to mitigate cisplatin-induced ototoxicity.Developing otoprotective agents that simultaneously reduce cisplatin resistance and enhance therapeutic efficacy holds significant implications for future treatment modalities. In this investigation, we evaluated the safety and efficacy profile of CSF1R inhibitor (PLX3397). Our findings demonstrate that PLX3397 confers otoprotection in cisplatin-induced ototoxicity through cochlear macrophage depletion, synergizes with cisplatin inhibited tumor cell survival, migration, and invasion in vitro. Additionally, it significantly suppressed xenograft tumor lesion growth and angiogenesis in zebrafish models while modulating the polarization state of tumor-associated macrophages in vitro and inducing tumor immune activation. Our findings suggest that PLX3397 represents a promising immunotherapeutic agent, and its combination with cisplatin may constitute a novel therapeutic strategy for attenuating cisplatin-induced ototoxicity while synergistically enhancing immunotherapy for Head and Neck Squamous Cell Carcinoma.