Abstract
Despite the demonstrated efficacy of immune checkpoint blockade therapies in various types of cancer, their efficacy in cervical cancer is limited. A crucial pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), is highly expressed in various types of cancers and contributes to tumor progression via the regulation of inflammatory responses and the tumor microenvironment. The present study aimed to explore the role of MIF in cervical squamous cell carcinoma (CSCC). Western blotting, reverse transcription-quantitative polymerase chain reaction, Cell-Counting Kit-8, flow cytometry and enzyme-linked immunosorbent assays were used to investigate the effects of MIF on CSCC progression and in the formation of inflammasomes using SiHa cells. Transcriptome and proteome sequencing were combined to screen for key effector proteins of MIF. Moreover, in vitro co-culture experiments were used to evaluate the roles of MIF and TSC22 domain family protein 3 (TSC22D3) as inflammatory tumor-promoting factors in macrophage recruitment and polarization induction. The results indicated that MIF was highly expressed in CSCC with lymph node metastasis, positively associated with cervical cancer stage, and associated with a poor prognosis. MIF was also found to promote the progression of CSCC cells and to be associated with inflammasome activation. Multi-omics screening results indicated that TSC22D3 may be an important MIF interacting factor. Moreover, MIF and TSC22D3 facilitated inflammasome activation, THP-1 cell migration and M2 polarization. Therefore, it is suggested that MIF and TSC22D3 may induce macrophage infiltration in cervical cancer lesions and affect the tumor microenvironment by polarizing macrophages toward the M2 phenotype, thereby promoting CSCC progression. The present study highlights the potential of the MIF-TSC22D3 axis as a novel therapeutic target, which could conceivably help to improve the efficacy of immunotherapy in the treatment of recurrent or metastatic cervical cancer.