Renal cell carcinoma (RCC) is a malignancy of the urinary tract originating in the tubular epithelium, accounting for approximately 80–90% of renal malignancies (1). It is the sixth and eighth most common cancer in both men and women (2). In recent years, its morbidity has increased at a rate of 1.6% per year. A poor prognosis is more common in men (3). At present, surgery remains the main treatment option for patients with RCC. However, about 25% of patients have middle or advanced-stage RCC or distant metastasis at the time of initial diagnosis. In addition, approximately 20–50% of patients with localized renal cell carcinoma eventually develop into metastatic renal cell carcinoma (mRCC), which is insensitive to conventional chemo-radiotherapy and exhibits multi-drug-resistance (4), resulting in a survival rate of less than five years after surgery for over 80% of patients (5).

In recent years, tumor immunotherapy has offered new treatment options for mRCC or advanced renal cell carcinoma (aRCC). Programmed cell death protein 1 (PD-1) is a member of the B7-CD28 co-stimulatory receptor family and is mainly expressed in activated T lymphocytes, B lymphocytes, and monocytes, while Programmed death-ligand 1 (PD-L1) is mainly expressed in tumor cells. These two molecules are specifically combined and showed abnormally high expression in tumor tissues, which is involved in the negative regulation of human immunity. They inhibit the survival and proliferation of T immune cells and the release of killer cytokines in the local microenvironment, as well as inducing cell apoptosis, thereby preventing the immune response against tumor cells and promoting the growth of tumor cells (6). PD-1/PD-L1 inhibitors can effectively block this effect, enhance the immune function of T cells, and exert immune function on tumor cells. Additionally, PD-1/PD-L1 inhibitors, as immune sentinel monoclonal antibodies, have been widely used in treating melanoma, lung cancer, lymphoma and kidney cancer, especially in treating mRCC or aRCC (7). Studies have shown that in renal cell carcinoma, PD-1/PD-L1 alone or in combination with conventional targeted drugs can improve anti-cancer efficacy and significantly extend survival rates (8). At present, based on IMmotion 010, CheckMate 025, CheckMate 214, and KEYNOTE-426 experiments, a multicenter randomized controlled study has been performed to evaluate the efficacy and safety of the single or combined use of PD-1/PD-L1 inhibitors in the treatment of mRCC or aRCC. However, its conclusions vary.

In this study, a systematic review of the published research literature on PD-1/PD-L1 inhibitors is conducted to comprehensively evaluate the clinical efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of mRCC or aRCC in an attempt to provide a rationale for the immunotherapy of mRCC or aRCC.

A total of 11 high-quality foreign randomized controlled trials in phase II and III were included in the systematical analysis and evaluation of the clinical efficacy and safety of PD-1/PD-L1 inhibitors alone or in combination in the treatment of mRCC or aRCC, with OS, PFS, ORR, PR, CR, DCR, and AEs as the outcome indicators. Firstly, in terms of total clinical efficacy, it was found that the experimental group was significantly better than the control group in OS, PFS, ORR, PR, CR, and DCR, indicating that the single or combined use of PD-1/PD-L1 inhibitors can produce better clinical benefits in the treatment of mRCC or aRCC, especially in terms of prolonging the OS and PFS of patients. Secondly, with regards to safety, no statistical significance was observed between the experimental group and the control group in terms of total AEs, stage I~II adverse reactions, or stage III~V adverse reactions, indicating that the PD-1/PD-L1 inhibitors alone or in combination did not increase the incidence of adverse reactions in patients, indicative of their safety. Although the incidence of adverse reactions, such as dysphonia, rash, hypothyroidism, arthralgia, and itching, in the experimental group was significantly higher than that in the control group, these reactions were deemed controllable. Therefore, in clinical treatment, these risks should be identified and subsequently avoided when treating mRCC or aRCC when using PD-1/PD-L1 inhibitors. It has been shown that the safety and tolerability of first-line VEGF inhibitors, including sunitinib, have been demonstrated in the treatment of renal cell carcinoma. And in this study, 7 of them were controlled studies with sunitinib group, and through my study, we found that PD-1/PD-L1 monotherapy or combination therapy group significantly prolonged OS, PFS, and improved ORR compared with sunitinib group, and significantly attenuated the incidence of AEs associated with any level of treatment. There are 2 papers with controlled studies with placebo group, and through my study, I found that there was no increase in grade 3 or higher treatment-related adverse events in the PD-1/PD-L1 mono or combination therapy group compared to the placebo group, which would suggest that combining PD-1/PD-L1 targeted agents is promising and does not increase drug toxicity. Thus, PD-1/PD-L1 monotherapy or combination therapy showed a very good safety profile in patients with advanced renal cell carcinoma. RCC, the twelfth most common cancer in the world (20), has no characteristic clinical features at the early stage. As a result, as many as 25% to 75% of patients develop distant metastases by the time of diagnosis, missing lifesaving opportunities for surgery. In addition, the prognosis of patients with mRCC or aRCC is always poor, with a five-year survival rate of less than 10% (21). Even with radical renal cancer resection, postoperative recurrence rates range from 10% in low-risk patients to 68% in high-risk patients (22). The widespread application of targeted therapy in cancer has greatly improved prognosis and prolonged the OS and PFS of kidney cancer patients (23). However, the efficacy of targeted drugs like sunitinib as a first-line medicine is not satisfied in the treatment of some mRCCs and aRCCs due to drug resistance (24). PD-1/PD-L1 serves as a common stimulator of the T cell immune response. When the PD-1/PD-L1 signaling pathway is activated, it can reduce damage to surrounding tissues by the immune response (25). In the tumor microenvironment, signaling overactivation can inhibit the proliferation and activation or apoptosis of CD4 and CD8T cells, thereby promoting the negative regulation of immunity and inhibiting the immune effect of T cells and lymphocytes. This will help tumor cells escape the surveillance of somatic immune response cells, eventually forming immune tolerance. It could mediate the immune escape of tumor cells and promote cellular growth and proliferation without immune prevention and control (26, 27). According to the guidelines of the European Society of Medical Oncology and the European Association of Urology (28), for clear cell renal cell carcinoma patients with medium- or high-risk operation, PD-1/PD-L1 inhibitors represented by pembrolizumab can be used to assist in postoperative radical resection or adjuvant immunotherapy with mRCC. This has also been shown to achieve good survival benefits in multicenter, randomized clinical trials of CheckMate 025, CheckMate 214, and KEYNOTE-426 (29, 30).

In this study, after systematically assessing and analyzing the seven outcome indicators of OS, PFS, ORR, PR, CR, DCR, and AEs, it was not difficult to find that, in terms of efficacy and safety, the OS, PFS, ORR, PR, CR, DCR, and AEs of the PD-1/PD-L1 inhibitor group, alone or in combination with the PD-1/PD-L1 inhibitor group, had a significantly better clinical efficacy and safety in the treatment of mRCC or aRCC than the control group. Significant heterogeneity was found in the analysis of PFS, and subgroup analyses were performed by PD-L1 expression, IMDC score, and the Memorial Sloan Kettering Cancer Center (MSKCC) score. As a result, it was found that the heterogeneity still existed, which would suggest that the heterogeneity of PFS may come from factors such as race, follow-up time, and sample size, which had less impact on our study in terms of the effectiveness of PFS. On the contrary, in terms of the heterogeneity of AEs, by classifying common adverse reactions by disease system and performing subgroup analyses, the results showed that the heterogeneity of adverse reactions, such as hairiness, rash, and dysphonia, was significantly reduced, and the burden of safety was significantly reduced compared with that of the control group, further indicating that the existence of heterogeneity of AEs could be eliminated by systematic subgroup analyses. It has been shown that racial differences exist in the clinical efficacy of cancer patients receiving targeted therapies in different regions, and the efficiency of patients with PD-1/PD-L1 inhibitors may vary depending on geographic location, which will likely be another important reason for the presence of heterogeneity. At the same time, we cannot ignore the following reasons for the existence of heterogeneity: (i) the sample size, population distribution, ethnicity, and tumor type of the included studies were quite different; (ii) there were differences in the traditional first-line chemotherapy regimen of patients receiving PD-1/PD-L1 treatment; (iii) most of the literature failed to specifically describe the random allocation method and allocation concealment, causing some non-blind results to the experimenter, investigator and experimental; (iv) in the experiment, the patient withdrew and lost to follow-up due to serious adverse reactions or other reasons. Therefore, we will continue to update the data and collect more high-quality clinical trials, especially in terms of medication regimen, duration of follow-up, type of disease, and ethnicity, to conduct a more detailed analysis to validate the data presented in this paper. But this study has the advantages of a long search time, the most comprehensive outcome indicators, the most recent data from literature studies and a large sample size compared with similar published literature, thus being a more objective and comprehensive outcome indicator for the analysis. At the same time, subgroup analyses were conducted for each outcome indicator, eliminating heterogeneity between studies and providing more objective and reliable guidance for clinical treatment.

In summary, the single or combined use of PD-1/PD-L1 inhibitors shows significant clinical benefits and safety in treating mRCC or aRCC. However, due to the limited number of articles, more high-quality, multicenter randomized clinical studies are needed to gain more comprehensive and sufficient medical rationales for treating mRCC or aRCC.