Cervical cancer (CC) is one of the most common malignancies among women and ranks fourth among all cancer-related deaths worldwide (1). In 2020, there were over 600,000 newly diagnosed cases of CC, with approximately 342,000 deaths, and the number of women under the age of 65 years being diagnosed with CC is also steadily increasing (2). In clinical settings, the treatment of patients with advanced, recurrent, or metastatic cervical cancer (ARMCC) is even more challenging. Despite various treatment options currently available for CC, including surgery, radiation therapy, chemotherapy, targeted therapy, and combination therapies (3), these approaches have limited survival rates and treatment effectiveness in patients with ARMCC. Therefore, there is an urgent need to develop novel therapeutic strategies.

Programmed cell death protein-1 (PD-1) inhibitors, which are a type of immunotherapy, have made significant breakthroughs in cancer treatment in recent years (4). PD-1 inhibitors inhibit the interaction between tumors and immune cells, enabling the patient’s immune system to better recognize and attack cancer cells. This novel class of drugs has been widely used to treat various types of cancers, including melanoma, lung cancer, and renal cell carcinoma, and has demonstrated remarkable clinical efficacy (5–7).

Some clinical studies have demonstrated the significant efficacy and survival advantages of PD-1 inhibitors in the treatment of cervical cancer, and current research is increasingly focusing on whether the combination of PD-1 inhibitors with other anti-tumor drugs can have better therapeutic effects in the treatment of CC.

However, no studies have investigated which specific anti-tumor drug, when combined with PD-1 inhibitors, yields the most effective results in the treatment of cervical cancer. This study aimed to provide comprehensive evidence of the efficacy of PD-1 inhibitors combined with other anti-tumor drugs in treating patients with ARMCC and to identify the patient population that benefits the most. Additionally, a comprehensive analysis of all adverse events (AEs) mentioned in the included studies was performed. This approach can provide clinicians with more accurate data and guidance when making decisions relating to treatment, ultimately leading to improved treatment strategies.

The binding of PD-L1, which is expressed on tumor cells or within the tumor microenvironment, to PD-1 on T cells leads to the suppression of T cell function, allowing cancer cells to evade immune surveillance and promote tumor development. Conversely, PD-1 inhibitors can reverse T cell dysfunction or apoptosis and maintain peripheral immune system tolerance, thereby exerting anti-tumor effects. This treatment strategy has shown significant success in the treatment of various malignant tumors and is transforming cancer therapy (5–7). As a significant category, PD-1 inhibitors have been approved for the treatment of various malignancies, including non-small cell lung cancer, malignant melanoma, and CC (30–33).

However, the therapeutic efficacy of PD-1 inhibitors for the treatment of CC, particularly ARMCC, remains controversial (20, 26). The key controversial issues include the following:1) Can the combination of PD-1 inhibitors with other treatment modalities significantly improve the therapeutic efficacy? For example, a combination of chemotherapy, anti-angiogenic agents, or other immunotherapies can effectively control tumor growth and spread. 2) Does the use of PD-1 inhibitors lead to severe adverse events? These adverse events can significantly affect the quality of life of patients with CC. Therefore, we conducted this study to address these issue. To the best of our knowledge, this study represents the first comprehensive analysis on the effectiveness and safety of PD-1 inhibitors combined with other anti-tumor drugs for the treatment of patients with ARMCC.

We found that, among the several treatment strategies for PD-1 inhibitor therapy in ARMCC, the combination of PD-1 inhibitors with chemotherapy exhibited the highest ORR. The combination of PD-1 inhibitors with anti-angiogenic agents exhibited the second highest ORR, followed by the combination of PD-1 inhibitors and CTLA-4 inhibitors. Finally, PD-1 inhibitor monotherapy resulted in the lowest ORR. In terms of the 1-year OS and 1-year PFS, various treatment strategies involving PD-1 inhibitor therapy in ARMCC have yielded similar results.

Based on the above results, it can be inferred that the treatment outcomes in ARMCC tend to favor the combination of PD-1 inhibitors with other anti-tumor drugs, such as chemotherapy, anti-angiogenic agents, or CTLA-4 inhibitors, rather than PD-1 inhibitor monotherapy. Evidence supports the suggestion that chemotherapy drugs and anti-angiogenic agents are able to disrupt tumor cells and release immunostimulatory tumor antigens, thereby enhancing immunogenicity (34). Our findings also confirmed that combination therapy enhanced the anti-tumor effects of PD-1 inhibitors.

According to a stratified analysis based on histological types and PD-L1 positive expression in ARMCC, the results revealed that in PD-1 monotherapy, the SCC and non-SCC groups did not exhibit a significant difference in terms of ORR. However, the group with a CPS≥1 exhibited a significantly higher ORR compared to the CPS<1 group. Additionally, when PD-1 inhibitors were used in combination with other anti-tumor drugs, the SCC group exhibited a significantly higher ORR than the non-SCC group. Moreover, the CPS≥1 group exhibited a higher ORR than the CPS<1 group, although the difference was not statistically significant. These findings suggest that SCC patients may benefit more from combined treatment with PD-1 inhibitors and other anti-tumor drugs, and patients with positive PD-L1 expression exhibit a better response to immunotherapy, which suggests that PD-L1 may be a potential biomarker for predicting clinical outcomes in patients with cervical cancer. Although a previous study indicated that PD-L1 expression levels did not enhance the OS and PFS of patients with ARMCC treated with PD-1 inhibitors (31), it is important to note that assessing the impact of drugs on OS and PFS can be confounded by the complex nature of the causes of death in patients with ARMCC, potentially introducing bias into the results. In contrast, ORR reflects the proportion of tumors that experience a rapid reduction or disappearance in volume within a short period of time, which provides a better indication of the therapeutic effect of drugs on tumors.

To enhance the credibility of our research findings, we conducted a meta-analysis of RCTs. The findings demonstrated that, compared to patients undergoing chemotherapy alone, the combination of PD-1 inhibitors with chemotherapy can significantly improve OS and PFS in patients with ARMCC. These results further support the superior efficacy of PD-1 inhibitors combined with chemotherapy compared to chemotherapy alone, and that more patients with ARMCC could benefit from them.

We also conducted a safety analysis and found that, on average, each patient with ARMCC who received PD-1 inhibitor treatment experienced approximately two adverse events. It is crucial to communicate these statistical data to patients before initiating PD-1 inhibitor therapy. The top five AEs in patients who received PD-1 inhibitor monotherapy were asthenia, diarrhea, hypothyroidism, pruritus, and elevated alanine aminotransferase levels. Similarly, patients who received PD-1 inhibitors in combination with chemotherapy experienced anemia, neutropenia, leukopenia, hypothyroidism, and constipation. Furthermore, patients who received PD-1 inhibitors combined with anti-angiogenic agents experienced hyperglycemia, hypothyroidism, anemia, diarrhea, and elevated aspartate aminotransferase levels. The top three ir-AEs in patients who received PD-1 inhibitor monotherapy were hypothyroidism, hyperthyroidism, and diarrhea. Similarly, patients who received PD-1 inhibitors in combination with chemotherapy experienced hypothyroidism, hyperthyroidism, and pruritus. Lastly, patients who received PD-1 inhibitors in combination with anti-angiogenic agents experienced hypothyroidism, immune-mediated hypothyroidism, and autoimmune thyroiditis.

We included three RCTs in the safety analysis to assess whether the use of PD-1 inhibitors would increase the incidence of AEs. The results showed that PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not increase the overall or severe AEs rates compared to chemotherapy alone. These findings are similar to a previous large-scale meta-analysis, which indicates the reliability of our analysis, despite our focus on only analyzing the AEs reported in the included literature (35).

This study has some limitations. First, most of the included studies were single-arm trials, which introduced a certain risk of bias and confounding factors owing to the lack of a control group. Even though we attempted to mitigate these risks through subgroup and stratified analyses, significant heterogeneity remained in some of the results. Second, in some of the included studies, data such as OS and PFS could not be utilized as the patients did not reach the median survival time, resulting in a less comprehensive survival analysis. Third, only one study on the use of PD-L1 inhibitors in combination with CTLA-4 inhibitors was included. Therefore, it is crucial to continue to monitor research related to PD-L1 inhibitors combined with CTLA-4 inhibitors to obtain more data that can be used to validate our results. Fourth, variations in PD-1 inhibitor use across studies in terms of therapy lines, combination regimens, treatment durations, and dosages may have increased outcome heterogeneity. Despite the significant heterogeneity, this study still holds value and significance.

Our study revealed that PD-1 inhibitors demonstrate outstanding efficacy in the treatment of patients with ARMCC. Patients with SCC may benefit more from treatments including PD-1 inhibitors in combination with other anti-tumor drugs. Additionally, PD-L1 may be a potential biomarker for predicting clinical outcomes in patients with cervical cancer. Importantly, the use of PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not lead to an increased incidence of AEs compared with chemotherapy alone, indicting safety during. Furthermore, identifying more subgroups of cervical cancer that benefit from PD-1 inhibitors is a direction worth researching.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

YW: Writing – original draft, Writing – review & editing. JW: Writing – original draft. JD: Writing – original draft. XT: Writing – original draft. JX: Writing – original draft, Writing – review & editing.