Objectives <p>Regarding the limited clinical curative efficacy of CD47-targeted immunotherapy in treating oral squamous cell carcinoma (OSCC), the project aims to study the effect and mechanism of imiquimod-enhanced CD47 targeting in treating OSCC.</p> Methods <p>The effect of imiquimod on enhancing the phagocytosis and clearance of OSCC cells of CD47 targeting was studied through phagocytosis experiments and cell clearance experiments. Then, the safety of the local application of imiquimod was confirmed, and the effect of imiquimod was verified in vivo by immunohistochemistry staining and tumor growth analysis. Finally, transcriptome sequencing, macrophage polarization, phagocytosis experiments, and cell clearance experiments were used to study the mechanism of imiquimod-enhanced CD47 targeting for treating OSCC.</p> Results <p>Imiquimod significantly enhances the phagocytosis and removal of OSCC cells when combined with CD47 targeting. In vivo studies have confirmed its capacity to potentiate CD47 targeting and revealed good biosafety of imiquimod. Mechanistically, imiquimod promotes M1 macrophage polarization by activating the Toll-like receptor (TLR)7-nuclear factor (NF)-κB pathway in macrophages. This activation enhanced the phagocytic capacity of macrophages to effectively remove OSCC cells.</p> Conclusions <p>Imiquimod enhances CD47 targeting in phagocytosing and removing OSCC cells by activating macrophage TLR7-NF-κB activation and subsequent M1 polarization, providing a promising approach for treating OSCC.</p>