Globally, cervical cancer ranks as one of the leading causes of cancer among women. According to the 2020 global cancer data released by the International Agency for Research on Cancer of the World Health Organization, there are 600,000 new cases and approximately 340,000 deaths due to cervical cancer worldwide. Cervical cancer ranks fourth in incidence and mortality among all female cancers and is the most prevalent gynecologic cancer [1]. Alarmingly, about two-thirds of cervical cancer patients are diagnosed at a locally advanced stage, with more than half of these individuals deemed clinically unsuitable for surgical intervention. This highlights the importance of prevention and early screening. Early human papillomavirus (HPV) vaccination can significantly reduce cervical cancer prevalence, and screening methods such as cervical cytology (Pap detection) and co-testing with HPV and cytology can detect cervical lesions early [2]. However, improving treatment strategies for these patients remains a critical issue.

The concurrent administration of radiotherapy and chemotherapy constitutes the standard treatment regimen [3]. However, despite advancements, the survival rate of cervical cancer has not significantly improved over the past five decades [4, 5]. While early-stage cervical cancer treatment with synchronous radiotherapy and chemotherapy shows promise, with a five-year overall survival (OS) rate of 65%, the prognosis for patients with advanced, recurrent, or metastatic cervical cancer remains bleak [6]. In these cases, the ability to control lesion metastasis falls short, and the five-year OS plummets to approximately 15% [7]. Despite undergoing standard treatment, the overall outlook for patients with locally advanced cervical cancer continues to be dismal [8, 9]. This underscores an urgent need for the development of new therapies to significantly enhance the prognosis for these patients.

In recent years, the field of oncology has seen remarkable advances with the advent of immunotherapy, particularly through the use of immune checkpoint inhibitors (ICIs). These innovative treatments have demonstrated significant efficacy across a broad spectrum of malignant tumors, introducing a novel paradigm in cancer therapy. Immune checkpoints serve as regulatory molecules within the human immune system, functioning as safeguards that temper the immune response by preventing the excessive activation of T cells, which could otherwise cause inflammatory damage. However, cancer cells can exploit this mechanism by over expressing these checkpoint molecules, effectively dampening the immune response and evading detection and destruction by the immune system, thereby facilitating tumor growth [10]. The most extensively researched and clinically applied ICIs target cytotoxic T lymphocyte associate protein-4 (CTLA-4), programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1). By inhibiting these immune checkpoints activity, ICI therapy lifts the “immune brakes” within the tumor microenvironment, reinvigorating T cells to recognize and attack tumor cells [11]. This approach has been particularly effective in cancers characterized by high mutation rates and dense T-cell infiltration, including melanoma and non-small cell lung cancer [12, 13].

Recently, the potential of ICIs for cervical cancer treatment has garnered attention, with numerous clinical trials highlighting their promising therapeutic impacts [14, 15, 16, 17, 18, 19]. These trials have explored various strategies, including ICI monotherapy, the combination of multiple ICIs, and the integration of ICIs with conventional chemotherapy, pointing toward novel avenues for cervical cancer treatment. However, the efficacy and safety of these treatment regimens are still unclear. Therefore, we conducted a meta-analysis of clinical trials focusing on cervical cancer to assess the effectiveness and safety of ICIs, aiming to provide a robust, evidence-based foundation for their clinical application.

Cervical cancer presents a substantial challenge to global public health, primarily due to its frequent late-stage diagnosis, leading to substantial rates of morbidity and mortality. Consequently, immunotherapy has emerged as a promising novel approach to treatment.

This study aimed to evaluate the efficacy and safety of ICIs in managing cervical cancer. Using predefined inclusion and exclusion criteria, we conducted an analysis of seven RCT [20, 21, 22, 23, 24, 25, 26]. The findings from these trials suggested that immunotherapy yields notable clinical benefits. Compared to conventional treatments, therapies involving ICIs have significantly prolonged OS and PFS in cervical cancer patients. However, our analysis did not reveal statistically significant differences in ORR, quality of life (QLQ-C30 scores), or the incidence of grade 3 or higher AEs. This means that the safety of ICI therapy appears to be comparable to conventional therapy. Subsequent sensitivity analyses confirmed the reliability of these findings. Our research results showed that the OS [HR = 0.68, 95% CI (0.60, 0.77); p 0.0001] and PFS [HR = 0.69, 95% CI (0.61, 0.78); p 0.0001] of patients in the study group was significantly higher than those in the control group, consistent with recent findings. Currently, numerous clinical trials are being conducted to assess the efficacy of ICIs in cervical cancer, with the majority prolonging OS, PFS, or higher ORR [27]. Compared to conventional therapies, ICIs provide a targeted approach to cancer therapy by modulating the immune system. They accomplished this by selectively blocking or attenuating the inhibitory signals of tumor cells to immune cells, thereby enhancing the immune system to attack the cancer [28]. One key advantage of ICIs over conventional methods such as radiotherapy and chemotherapy lies in their potential for long-term benefits. Unlike the transient effects of radiotherapy and chemotherapy, ICIs can induce the immune system to develop a durable memory. Consequently, even after treatment completion, the immune system remains vigilant, capable of identifying and combating any potential cancer recurrence [29]. This mechanism underlies the ability of ICIs to extend both PFS and OS. Additionally, ICIs hold promise across a broad range of cancer types, particularly those traditionally resistant to radiotherapy and chemotherapy. In such instances, the potential impact of ICIs on prolonging OS and PFS may be even more significant, providing renewed optimism for patients contending with cancers resistant to conventional therapies.

Previous studies have indicated that combination therapy involving ICIs may yield superior efficacy compared to ICI monotherapy. Some substances released following radiotherapy-induced tumor cell death can induce tumor-specific immune response to continue killing tumor cells, and ICIs can improve the therapeutic effect of radiotherapy by reversing the immunosuppression of tumor microenvironment [30, 31]. The synergistic effect has been validated in clinical studies of stage III non-small cell lung cancer [32]; however, research on cervical cancer remains relatively scarce. Currently, an ongoing phase II clinical study (NCT03614949) has drawn attention because of its novel approach involving atezolizumab combined with radiotherapy for cervical cancer [33]. Chemotherapy can release tumor antigens and alleviate immune suppression induced by tumor cells. The combination of chemotherapy and ICIs has been shown to significantly augment central and effector memory T cell populations, thereby fostering persistence [34].

In contrast, monotherapy is prone to triggering additional immune evasion mechanisms that contribute to primary or adaptive drug resistance [35]. However, this study did not demonstrate the superior efficacy of combination therapy compared to monotherapy with ICIs. However, given the limited number and characteristics of the included studies, it is premature to definitively conclude the absence of such superiority. Further research is warranted to thoroughly investigate this promising therapeutic strategy.

In addition, it is noteworthy that the majority of drugs in our included studies were PD-1 and PD-L1 inhibitors. This could be partly attributed to our deliberate focus on “PD-L1 inhibitors” as a key search term during our literature review. This reflects the current research trend towards PD-1/PD-L1 inhibitors, which, alongside CTLA-4 inhibitors, constitute the forefront of immune checkpoint inhibition in cancer treatment. Notably, the approval of the PD-1 inhibitor Pembrolizumab by the US Food and Drug Administration (FDA) in 2018 as a second-line treatment for PD-L1 positive cervical cancer (combined positive score $\ge$1) patients was followed by its additional endorsement in 2021 for first-line treatment in combination with chemotherapy $\pm$ bevacizumab for cervical cancer [3]. Our review encompassed the timeframe from 2019 to 2023, with specific attention directed towards the years 2022 and 2023. It is probable that this timeframe influenced the prominence of pembrolizumab in the studies we analyzed, thus underscoring its pivotal role in ongoing research pertaining to cervical cancer treatment.

Indeed, there are other PD-1 and PD-L1 inhibitors undergoing clinical trials, such as the PD-1/CTLA-4 inhibitor Cadonilimab, the PD-1 inhibitor Zimberelimab and Nivolumab [36]. At the same time, recent years have witnessed the discovery of more immune checkpoints, such as lymphocyte activation gene-3 (LAG-3), t cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and cluster of differentiation 47 (CD47) [37, 38, 39, 40]. Inhibitors targeting these proteins are presently undergoing preclinical or clinical investigation, and hold promise for potential utilization in cervical cancer treatment in the future. These aspects merit further examination and discussion in subsequent investigations.

Regarding the results of our data analysis, we observed significant heterogeneity in ORR and QLQ-C30 scores. Given the limited number of included studies, subgroup analysis was not feasible. The increased heterogeneity might stem from the diversity of drugs and treatment strategies in the evaluated trials. It is noteworthy that two particular studies [23, 25], which significantly contributed to the increase in heterogeneity, were not blinded to participants and researchers. The impact of this lack of blinding cannot be overlooked. Other factors, such as baseline characteristics and histologic classification, may also have contributed to the observed heterogeneity.

In addition, it is worth noting that not all included studies reported the expression of PD-L1 in tumor cells, which can greatly affect the effectiveness of the corresponding drugs. Some studies observed significant anti-tumor activity only in PD-L1 positive patients [41]. High PD-L1 expression in tumor cells suggests a greater possibility of tumor immune escape via PD-1/PD-L1 signaling pathway, increasing the potential efficacy of PD-1/PD-L1 inhibitors. Consequently, the differences in treatment efficacy between studies may be partly due to varying levels of PD-L1 expression in the included populations. This hypothesis requires further investigation.

There were several limitations in this meta-analysis. First, the studies reviewed focused on a narrow range of drug types, limiting our ability to fully assess the efficacy and safety of ICI therapy for cervical cancer treatment. Second, the number of included studies is relatively small. The lack of comprehensive histologic data on cervical cancer restricted our analysis concerning the efficacy of ICIs across different histologic types. For a more thorough evaluation of the efficacy and safety of ICIs in the treatment of cervical cancer and to tailor treatments more precisely, future research should include a broader spectrum of ICIs beyond PD-1/PD-L1 inhibitors. Further investigations into the efficacy of ICI therapy across different histologic types of cervical cancer are also necessary. To refine treatment approaches, more studies comparing the efficacy and safety of combination therapy versus monotherapy are also essential. Finally, further analyses of PD-1/PD-L1 inhibitors should consider the expression of PD-L1 in tumor cells, which will help identify patients who are more suitable for ICI therapy.

In summary, patients receiving immunotherapy reported a delayed onset of symptom deterioration and an improvement in overall survival rate, although the incidence of severe AEs appears to be comparable to those observed with traditional treatments. These findings suggest that immunotherapy may offer a more favorable option for cancer patients. Despite these promising results, more research and randomized clinical trials are needed to validate these initial findings.

All data points generated or analyzed during this study are included in this article and there are no further underlying data necessary to reproduce the results.

CL designed the research study. XZ and YZhan extracted and analyzed the data, and drafted the manuscript. YZhou designed the chart. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research was supported by the Natural Science Foundation of Sichuan province (2024NSFSC1673).

The authors declare no conflict of interest.