SPP1 enhances radiotherapy resistance through CCL2-mediated M2-like polarization of macrophages in cervical Cancer

Abstract

Late-stage cervical cancer often exhibits poor responses to radiotherapy and immunotherapy, but the key regulatory factors and mechanisms underlying these issues remain inadequately understood. In the current study, we reveal that the expression level of SPP1 correlates positively with pathological grading, and patients with higher SPP1 expression show poorer response to radiotherapy and worse clinical outcomes. Analysis of clinical dataset reveals that SPP1 expression is associated with M2-like polarization of tumor-associated macrophages, a process known to closely relate to resistance against tumor immunotherapy. In co-culture systems of cervical cancer cells and macrophages, either knockdown or overexpression of SPP1 can correspondingly inhibit or promote M2-like polarization. RNA-seq data analysis of SPP1 knockdown cervical cancer cell lines indicates that SPP1 enhances the expression of CCL2, a crucial factor that drives M2-like polarization of macrophage. In vivo experiments demonstrate that inhibiting SPP1 expression in cervical cancer effectively suppresses p-STAT3 expression level and M2-like polarization of macrophages, thereby alleviates cervical tumor progression. Our study elucidates the mechanism by which SPP1 contributes to progression of cervical cancer and provides a theoretical basis for the development of targeted therapeutic strategies aimed at advancing precision medicine.

Keywords: CCL2; Cervical Cancer; M2-like polarization; Radiotherapy resistance; SPP1.