Progress and prospects of the combination of BMI1-targeted therapy and immunotherapy in cervical cancer.

Am J Cancer Res 2025;15(1):217-232 www.ajcr.us /ISSN:2156-6976/ajcr0160491 Review Article Progress and prospects of the combination of BMI1-targeted therapy and immunotherapy in cervical cancer Yingying Chen1,2, Shiyu Liu1,2, Xia Yin1,2 Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, P. R. China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, P. R. China 1 Received September 12, 2024; Accepted January 14, 2025; Epub January 15, 2025; Published January 30, 2025 Abstract: Cervical cancer is one of the most prevalent gynecologic malignancies, posing a significant threat to women’s health and survival. Despite advancements in early screening and diagnosis, which have led to cervical cancer being termed a “preventable” cancer, treatment options for advanced and recurrent cervical cancer remain limited. Consequently, identifying new therapeutic targets and treatments is crucial for advancing the research and management of cervical cancer. In recent years, targeted therapy and immunotherapy have become focal points in oncology research, offering new avenues and directions for the treatment of cancer. Preclinical studies have demonstrated that targeting BMI1 can inhibit cervical cancer progression, while immunotherapy has advanced to phase III clinical trials, showing promising results. To date, there have been no reports on the combination of BMI1-targeted therapy and immunotherapy in cervical cancer. This review, therefore, elucidates the current state of research and explores the potential and perspectives of combining targeted therapy with immunotherapy for cervical cancer. Keywords: BMI1, cervical cancer, targeted therapy, immunotherapy, PTC596 Introduction Cervical cancer, the most common malignant gynaecological cancer, is a major global health problem and a major cause of disability adjusted life years [1]. It mainly affects women in developing countries, and studies have found it to be associated with persistent infections with high-risk human papillomavirus (HPV) types. The prevention and early diagnosis and treatment of cervical cancer has developed rapidly due to the popularity of cervical cancer screening technology and the attention paid to the disease and the use of HPV vaccine nowadays [2]. The stage of cervical cancer at diagnosis strongly influences treatment approaches and outcomes for cervical cancer patients. According to statistics, the 5-year overall survival rate for all stages combined is 67%: 91% for early stage, 60% for locally advanced disease, and 19% for metastatic disease [3]. Therefore, the treatment of advanced cervical cancer and recurrent and metastatic cervical cancer has become a key and difficult issue in the treatment of cervical cancer. With the recent approval of a PD-1 blocking antibody for recurrent or metastatic disease, immunotherapy offers a new method for cancer treatment. Clinical studies on cervical cancer have been conducted since 2015. The notable KEYNOTE-158 phase II clinical trial investigated the use of pembrolizumab as a monotherapy in cervical cancer [4]. Based on the results of this study, the FDA approved pembrolizumab for the treatment of cervical cancer [4]. With more and more in-depth research on immunotherapy for cervical cancer, immunotherapy has also become a second-line treatment strategy for replaced cervical cancer. Recent years, more and more researches demonstrated that BMI1 significantly overexpressed in many cancers including cervical cancer. Targeting BMI1 in a variety of ways, including induction of autophagy-mediated necrosis, inhi- https://doi.org/10.62347/QTWJ8918 BMI1-targeted therapy and immunotherapy in cervical cancer Figure 1. Schematic diagram of the pathogenesis of cervical cancer. Persistent infection of normal cervical epithelium with HPV causes the cervical epithelium to overexpress HPV oncoproteins E6 and E7, gradually leading to malignant transformation of the cervical epithelium. bition of epithelial-mesenchymal transition and regulation of tumor immunoenvironment, dramatically reduces cancer proliferation and metastasis [5]. BMI1 expression levels are closely correlated with the histological grading of cervical cancer, and the inhibition of cervical cancer cell proliferation, colony formation, and lymph node metastasis [6]. And in other cancer research, BMI1 can enhance the infiltration and activity of CD8+ T cells in the tumor microenvironment, and improve the immunotherapeutic efficacy of PD-1 inhibitors, thereby preventing immune escape [7]. This review explores the potential synergistic effects of BMI1 inhibition and immunotherapy, with the goal of addressing existing therapeutic limitations. Addressing the intricate tumor microenvironment and resistance mechanisms of cervical cancer, this combined approach could provide more effective and sustainable treatment solutions for patients. Current status of cervical cancer Cervical cancer is the most prevalent gynecologic malignancy, ranking fourth among all female cancers, posing a significant threat to 218 women’s health and lives [8]. Over 500,000 women are diagnosed with cervical cancer annually, with over 300,000 deaths occurring globally each year [9]. Most cervical cancers are linked to persistent infections with high-risk HPV types, such as 16 and 18. HPV screening and vaccination programs have become effective strategies for cervical cancer prevention [10]. Persistent high-risk HPV infection causes cervical epithelial cells to overexpress the oncoproteins E6 and E7, which inhibit the tumor suppressors p53 and Rb, respectively, leading to the malignant transformation of cervical epithelium [11] (Figure 1). These oncoproteins also inhibit apoptosis, destabilize the genome, prevent telomere shortening, promote angiogenesis, and facilitate the invasion and metastasis of cervical cancer [12]. Squamous cell carcinoma and adenocarcinoma are the most common histological subtypes of cervical cancer, comprising approximately 70% and 25% of cases, respectively [13]. Despite advances in prevention, screening, diagnosis, and treatment over the past decade, significant regional and global disparities persist in cervical cancer treatment outcomes. These disparities prompted the International Gynecologic Cancer Am J Cancer Res 2025;15(1):217-232 BMI1-targeted therapy and immunotherapy in cervical cancer Figure 2. The expression of BMI1 in paired samples of cervical tissue from public databases (TCGA and GTEx). Society to publish evidence-based management guidelines aimed at improving patient care quality [14]. The treatment of advanced and recurrent cervical cancer remains clinically challenging, prompting researchers to explore new therapeutic approaches. Association between BMI1 and cervical cancer Overview of BMI1 The B lymphoma Mo-MLV insertion region 1 homolog (BMI1) gene was f (...truncated)