The Dual Role of Cellular Senescence in Cervical Cancer

Abstract

Cellular senescence is an irreversible cell cycle arrest state that exerts dynamic dual regulatory effects on the occurrence, treatment, and prognosis of cervical cancer through the activation of tumor suppressor pathways such as p16INK4a/p53 and the secretion of senescence-associated secretory phenotype (SASP) factors. In the precancerous lesion stage, senescence acts as a natural anti-tumor barrier by inhibiting the proliferation of cells infected with high-risk human papillomavirus (HPV) and eliminating genomically unstable cells, thereby delaying the progression of cervical intraepithelial neoplasia (CIN). However, in the tumor progression stage, senescent cells can remodel the tumor microenvironment (TME) by releasing SASP-related factors, promoting immunosuppression (such as recruiting Treg cells), angiogenesis, and epithelial-mesenchymal transition (EMT), thereby driving invasion and metastasis. Moreover, although conventional treatments such as radiotherapy and chemotherapy can induce tumor cell senescence and inhibit proliferation, the remaining senescent cells may enhance the stemness and drug resistance of adjacent tumor cells through paracrine signaling. Therefore, a comprehensive understanding of the dynamic regulatory mechanisms and conflicting functions of cellular senescence at different stages of cervical cancer, along with its therapeutic-induced tumor-suppressive effects, is crucial for developing novel treatment strategies targeting senescence pathways. This includes exploring senescence induction to eliminate high-risk cells during precancerous lesions, or applying senolytics (drugs that selectively clear senescent cells) and senomorphics (drugs that inhibit harmful SASPs) in established tumors. These approaches aim to overcome treatment resistance, improve prognosis, and achieve more precise cervical cancer prevention and control. This article systematically reviews the dynamic regulatory mechanisms and contradictory functions of cellular senescence in cervical cancer and explores the potential value of targeting senescence pathways in treatment.