Ovarian cancer (OC) is the second leading cause of female gynecological cancer death worldwide (Bray et al., 2020). It was estimated that 313,959 people were diagnosed with OC and 207,252 people died of OC in the world in 2020 (Global, 2020; Siegel et al., 2021). The early symptoms of OC were insidious, and most of the patients were advanced at the time of treatment. Traditional treatment for OC was mainly surgery plus adjuvant chemotherapy, while the emergence of chemotherapy resistance affects the prognosis of patients to a certain extent, so the median survival period of advanced/recurrent epithelial OC is only 14.6 months (Shimokawa et al., 2018). The latest concept pointed out that the treatment for OC can be evolved into the treatment for chronic diseases, and the future treatment mode of OC will gradually move towards the trend of combined treatment, including surgery, chemotherapy, endocrine therapy, immunotherapy, and other methods (Ovarian, 2022).

Tumor immunotherapy is the fourth anti-tumor therapy after surgery, chemotherapy, and radiotherapy. In the tumor microenvironment, tumor cells express corresponding ligands, thus leading to T cell dysfunction, which enables tumor cells to escape the surveillance and clearance of the immune system. Targeted drugs against cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death receptor 1 (PDCD1, also known as PD-1)/programmed cell death receptor ligand 1 (PDCD1LG1, also known as PD-L1) play an anti-tumor effect by relieving tumor cells’ inhibition of T cell function (O'Donnell et al., 2017). In recent years, immune checkpoint inhibitors (ICI), as the most common immunotherapy, have brought hope for treating malignant tumors (Boustani et al., 2021).

On 17 August 2021, Food and Drug Administration (FDA) approved Dostarlimab-gxly (JEMPERLI) for adult patients with dMMR, relapsed, or advanced solid tumors who have progressed on or after prior therapy and had no satisfactory alternative therapy. (Markham, 2021). In September 2021, the National Comprehensive Cancer Network (NCCN) guidelines were recommended for use in the guidelines for uterine tumors and ovarian cancer. In 2022, the NCCN guidelines recommended that the indications for using PD-1/PD-L1 inhibitors in advanced/recurrent OC mainly include: Tumor tissue is in deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) state, and tumor mutation burden-high (TMB-H ≥10 muts/MB) (Ovarian, 2022).

The effects of PD-1/PD-L1 inhibitors, such as Nivolumab, Pembrolizumab, Avelumab, and Atezolizumab, have been confirmed by clinical studies (Brahmer et al., 2012; Hamanishi et al., 2015; Disis et al., 2019; Liu et al., 2019; Matulonis et al., 2019; Normann et al., 2019; Varga et al., 2019; Desai et al., 2020; Hamanishi et al., 2021; Pujade-Lauraine et al., 2021). Most of these tests are designed as single arm tests, and the form is irreparable. Therefore, we conducted a meta-analysis to investigate the efficacy of anti-PD-1/PD-L1 alone in OC.

In this study, 11 studies, involving 990 patients, were analyzed to evaluate the efficacy of PD-1/PD-L1 inhibitors in the treatment of recurrent/refractory OC. Our results indicated that in patients with recurrent/refractory OC, PD-1/PD-L1 inhibitors were used alone and there was no obvious evidence for the improvement of efficacy and survival. As for safety, the incidences of TRAEs and iAEs are high, so PD-1/PD-L1 inhibitors should be applied based on individual conditions.

Currently, the 2022 NCCN guidelines show that PD-1/PD-L1 inhibitors are effective in some cases of recurrent epithelial OC (including rare pathological types) and recurrent malignant germ cell tumors, but PD1/PD-L1 inhibitors are not recommended for recurrent malignant sex cord stromal tumors. Therefore, in the case of unsatisfactory effects of surgery, chemotherapy and other treatment methods, immunotherapy can be considered for such patients (Ovarian, 2022). However, the guidelines only recommend that patients with MSI-H/dMMR may benefit from immunotherapy. Although PD-1/PD-L1 inhibitors have made breakthrough progress in the treatment of gynecological tumors, the current immunotherapy effect in OC is still not satisfactory or perfect. The reasons are closely related to the immune escape mechanism of OC and the changes of tumor immune microenvironment (TIME): 1) Recognizing related antigens is weakly developed: Among various cancers, including OC, NY-ESO-1 is considered as a promising and effective target for immunotherapy (Gordeeva, 2018). Some studies revealed that no NY-ESO-1 peptide antigen was found in major histocompatibility complex (MHC-1) or MHC-2 molecules in 42 epithelial OC samples (Schuster et al., 2017). In clinical trials of OC, many solid tumor targets rely on tumor related antigens that have been discovered, such as HER2, WT1, NY-ESO-1, and p53, while they do not all exist on MHC molecules. Meanwhile, these studies has not been proved that the tumor antigens in question do not get processed and presented on MHC-1 or MHC-2 molecules. Therefore, the induction of immune response against these antigens may mislead immune cells, and thus prevent them from attacking tumor cells. 2) Inhibition of antigen presenting cells: Antigen presenting cells include macrophages, dendritic cells, and B lymphocytes. Severe dysfunction of dendritic cells occurs in advanced OC. Cancer cells infiltrate dendritic cells in large quantities and secrete PGE2 and TGF- β. By inducing PD-L1 and arginase activity, normal dendritic cells with immune function can be transformed into immunosuppressive cells (Chae et al., 2017). 3) Inhibition of tumor killing immune cells and activation of immunosuppressive cells: Regulatory T cells (Tregs) can inhibit the anti-tumor response of T cells. Tregs negatively regulates anti-tumor response in a direct and indirect manner (Mishra et al., 2021; Puleo and Polyak, 2022). Curiel et al. confirmed that CD4⁺CD25+FOXP3+Tregs specifically inhibited anti-tumor T cells in vivo and promoted tumor growth (Curiel et al., 2004). Their existence is correlated with the poor prognosis of OC. Myeloid derived suppressor cells (MDSCs) have a significant ability to inhibit T cell response (Lim et al., 2020), and they increase in OC patients and play an important role in disease progression. 4) The mechanisms of the OC immunosuppressive network include the inhibition of CD8+effector T cells by Tregs, as described previously. Secondly, indoleamine-2, 3-dioxygenase (IDO), an immune regulatory enzyme, induces immune tolerance by locally consuming tryptophan and producing toxic tryptophan metabolites (such as kynurenine), thus resulting in the growth of effector T cells or NK cells in TME that is hindered and inhibits their killing function. IDO inhibitors can improve the anti-tumor efficacy of current chemotherapy or immunotherapy (Zhai et al., 2020); The most classical inhibition pathway is the combination of inhibitory immune checkpoint CTLA4 and PD-1 with ligand PD-L1; in addition, MDSCs and inhibitors, such as TGF- β, also participate in regulating the immunosuppressive network of OC (Odunsi, 2017).

Future research directions of immunotherapy are displayed as follows. Most preclinical and clinical studies focus on recurrent/metastatic/persistent/late unresectable gynecologic tumors (Brahmer et al., 2012; Hamanishi et al., 2015; Disis et al., 2019; Liu et al., 2019; Matulonis et al., 2019; Normann et al., 2019; Varga et al., 2019; Desai et al., 2020; Hamanishi et al., 2021; Pujade-Lauraine et al., 2021). However, more and more evidence supports that it should be used as early as possible when the patients are in generally good condition and the tumor load is small. In recent years, studies have suggested that early application of PD-1/PD-L1 inhibitor in the treatment of triple negative breast cancer and non-small cell lung cancer could benefit patients (Topalian et al., 2020). Another highly concerned treatment direction is combination therapy. Research in OC illustrated that the ORR of the combination of PD-1/PD-L1 inhibitors and chemotherapy was the highest [36% (95% CI: 24%, 51%)], the ORR of the combination of PD-1/PD-L1 inhibitors and anti-angiogenesis therapy was 30% (95% CI: 19%, 44%), and the ORR of the combination of PD-1/PD-L1 inhibitors and poly adenosine diphosphate ribose polymerase (PARP) inhibitors was 17% (95% CI:11%, 26%) (Zhu et al., 2021). However, the combined use of multiple drugs is like a double-edged sword, which brings about a new problem: the toxic and side effects of drugs. Compared with the existing PD-1/PD-L1 inhibitor combined with chemotherapy, this study showed that the single drug treatment of PD1/PD-L1 inhibitor could not significantly reduce the incidence of serious adverse reactions. Therefore, how to achieve the best treatment effect for patients with the least toxic and side effects is an urgent problem to be solved in the combined application of PD-1/PD-L1 inhibitors. It is also one of the research directions in the future to explore more effective predictors. At present, clinical efficacy predictors include dMMR/MSI-H, PD-L1, and TMB-H, but these predictors are not ideal. On the one hand, it is because the ORR of PD-1 inhibitor is poor, even in PD-L1 positive OC patients (Varga et al., 2019). On the other hand, KEYNOTE-100 shows a low MSI rate in OC (Matulonis et al., 2019), and the TMB of OC patients is also very low.

Moreover, before using immunotherapy, we should carefully consider the patient’s sociological factors, lifestyle, metabolic disorders, and other variables, aiming to obtain the best treatment results. In this study, it showed that race, obesity, smoking, exercise, and drinking habits affect the effectiveness of immunotherapy, while diabetes and hypertension are the results of immunotherapy, rather than the causes. Hormone signaling also affects prostate cancer, endometrial cancer, OC, and colon cancer. It is imperative to determine the hormone response profile of individual tumor in the context of ICI therapy (Deshpande et al., 2020).

Zhu J et al. pointed out that PD-1/PD-L1 inhibitors alone have limited efficacy in OC. PD-1/PD-L1 inhibitor combined with chemotherapy can be recommended for further research. Compared with their research, this study further explored the safety of immunotherapy, the immune escape mechanism of OC and the efficacy of various types of PD-1/PD-L1 inhibitors on OC (Zhu et al., 2021).

This study has some limitations. First, most of the articles included were non-comparable, and include phase I–III clinical studies, which makes this study have certain heterogeneity. Second, PD-1/PD-L1 inhibitors are different in the study, which inevitably leads to deviation. Third, there is not enough data to evaluate the patient’s Body Mass Index, allergy history, race, drinking history, smoking history, and other characteristics.

To our knowledge, this meta-analysis is the first to focus on the efficacy of PD-1/PD-L1 inhibitors alone in recurrent/refractory OC, which is timely and necessary. According to this study, the efficacy and safety of PD-1/PD-L1 inhibitors in patients with recurrent and refractory OC are not satisfactory, which is far from the role of PARP inhibitors and immunotherapy in the treatment of metastatic and recurrent cervical cancer. At present, we often put PD-1/PD-L1 inhibitors in the post-treatment of OC. When other drugs are not effective, PD-1/PD-L1 inhibitors can be used alone or in combination with other drugs according to the patient’s genetic status.