Renal cell carcinoma (RCC) is one of the common urological cancers, accounts for approximately 2% of all malignancies, with an estimated 431,288 new cases and 179,368 deaths in 2020 worldwide (1). Although most patients are localized disease and could undergo surgical resection with curative intent, about one-third of patients will develop metastatic disease recurrence (2, 3). Furthermore, 30% of patients present regional or distant metastases at initial diagnosis (2). Over the last decades, advancements in the treatment of metastatic RCC (mRCC) improved patients’ prognosis dramatically, such as the tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICIs) (4, 5).

With the progress of the management of mRCC, identification of predictive markers would be of great value to patients’ treatment and long-term outcomes. The International metastatic renal cell carcinoma Database Consortium (IMDC) risk model is widely used for mRCC patients’ stratification and treatment selection. Recently, other potential biomarkers have been investigated for their prognostic and predictive value, including programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), molecular and genomic signatures, and clinical factors (6).

Evidences suggested that host inflammation response plays an important role in cancer progression by enhancing tumor angiogenesis and metastasis (7, 8). Peripheral blood parameters might reflect the cancer-related inflammatory phenomena. Previous reported have reported that prognostic value of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutrition index (PNI), and systemic immune-inflammation index (SII) in many cancers (9–12).

The SII is defined as follows platelet count × neutrophil count/lymphocyte count and has been found to be associated with the prognosis of several cancers, such as urothelial carcinoma, hepatocellular carcinoma, and non-metastatic RCC (12–14). The prognostic value of SII in mRCC patients treated with systemic therapy remains unclear. Therefore, we summarized all relevant studies and investigated the prognostic significance of SII in mRCC.

At first, 594 articles were identified based on the electronic database search. After excluding the 74 duplicated articles, the remaining 520 records were screened. According to the titles and abstracts, 66 studies were further reviewed detailedly. At last, a total of 12 studies incorporating 4,238 patients were included in the final analysis (19–30). The detailed information was illustrated in Figure 1 ( Supplementary Table S1 ).

In the present study, we evaluate the association between SII and mRCC patients, observing that high SII was associated with the poor prognosis of mRCC. When stratified by therapies, high SII also predicts an inferior OS and PFS in mRCC patients treated with TKI or ICI. Moreover, we performed subgroup analysis and found all subgroup results are consistent with overall results. We only included the studies that provided the largest and newest data, which may affect the totality of data. However, this would likely be non-differential given the prognostic nature of the studies.

Local recurrence or metastasis is highly likely to occur in the RCC, nearly 30% of patients will develop local or distant recurrence after surgery (3). Meanwhile, one-third of patients suffer from metastasis initially (2). Although systemic therapy achieved great improvement of mRCC patients’ survival, not all patients could respond to these therapies. Many efforts to explore predictive markers are continuing.

The association between inflammation and malignancy has been widely explored in the past decades. Lots of studies have revealed an immunogenic nature of RCC (31). This immunogenic microenvironment may explain the antitumor efficacy of immune-related therapy used in mRCC treatment. While, the tumor infiltrating cells and their secretions may play a role in tumorigenesis, progression and clinical outcomes (32). It has been revealed that some peripheral markers of inflammation, NLR, PLR, and CRP were associated with prognosis of mRCC patients (33). Yucel et al. collected 706 mRCC patients treated with first-line TKI from multicenter and observed that pre-treatment high SII was considered a predictor of poor OS (HR = 1.39; P = 0.01) and PFS (HR = 1.60; P < 0.001) (23). In addition, SII might provide the similar predictive value as the IMDC and MSKCC, with the similar C-index values for OS and PFS in SII, IMDC, and MSKCC risk scores (23). Bugdayci Basal et al. demonstrated that in different IMDC risk groups, the patients with higher SII had a significantly worse OS compared with those with lower SII. And the SII may increase the predictive value of IMDC risk model in mRCC patients treated with TKI (24). Chrom et al. demonstrated that the addition of the SII to the IMDC model in place of neutrophil and platelet counts increased the model’s prognostic performance (27). Moreover, for mRCC patients received ipilimumab plus nivolumab in the first-line setting, high SII was also an unfavorable factor for OS and PFS (22). A prospective cohort of patients with mRCC treated with nivolumab also revealed that SII independently predicted OS (HR = 2.99; P < 0.001) (28). Recently, a retrospective study of 1,034 mRCC patients from 56 centers also revealed that a high SII is associated with poor oncological outcomes in patients treated with first-line immune combinations therapy (30). Wang et al. performed a meta-analysis and explored the prognostic value of SII in cancer patients receiving ICI. They found SII could predictive OS and PFS irrespective the cancer type, ICIs type and cutoff value of SII (34). Based on the abovementioned evidence, high SII could be served as an unfavorable factor in mRCC patients treated with systemic therapies. However, more large-scale studies are required to verify our findings.

The potential mechanism for the prognostic significance of this combination might be explained by the functions of neutrophil, platelet, and lymphocyte. Neutrophils can promote cancer development through directly interacting with tumor cells. Neutrophils can secrete proinflammatory cytokine and chemokine related to the remodeling of the tumor microenvironment and have a tumor-promoting effect (35). Platelets have been reported to regulate tumor angiogenesis, protect tumor cells from cytolysis, and contribute to tumor metastasis (36). As a major cellular immunity component in humans, lymphocytes are implicated in killing the host cancer cells by cell-mediated immunization. Therefore, the decreased lymphocytes may cause a weak anti-tumor activity and lead to cancer progression (24).

SII had significance in clinical practice. SII was calculated based on the neutrophil, platelet, and lymphocyte, which is convenient, easily obtained and commonly tested before the treatment. SII could predict the prognosis of patients, which could be used for mRCC patients’ managements. However, the individual conditions should be considered during the treatment strategy decision.

Our study is not devoid of shortcomings. First of all, total 12 studies consisting of 4,238 patients were included, which is not a relatively large sample and may limit the power of final results. Next, almost all studies were retrospective studies with the potential inherent bias, resulting heterogeneity. Therefore, we conducted sensitivity analysis and subgroup analysis. We only included the studies that provided the largest and newest data, which may affect the totality of data. But this would likely be non-differential given the prognostic nature of the studies. At last, although we performed subgroup analyses and meta-regression, there are several factors that are not available and may result heterogeneity such as detailed treatments and comorbidity, so we could not conduct additional analyses.

In conclusion, high SII could serve as an unfavorable factor in patients with mRCC treated with systemic therapy. Stratified by therapies, the elevated SII was also associated with worse prognosis. Whereas, more prospective and large-scale studies are warranted to validate our findings.

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

JX: Writing – original draft, Methodology, Formal analysis, Data curation. PC: Writing – original draft, Methodology, Formal analysis, Data curation. SC: Writing – original draft, Methodology, Formal analysis, Data curation. XH: Writing – original draft, Data curation. XL: Writing – review & editing, Supervision, Investigation, Conceptualization.