This meta-analysis aimed to investigate the prognostic significance of serum CysC levels in RCC patients. It incorporated five eligible retrospective studies involving a total of 1641 individuals. The findings revealed that patients with high preoperative serum CysC levels exhibited shorter OS and DFS compared to those with low preoperative serum CysC levels. Multivariate analysis further indicated that preoperative serum CysC levels served as an independent predictor for OS and DFS in patients with RCC. Consequently, preoperative CysC levels can be regarded as a prospective indicator for predicting patient’s survival.

CysC was encoded by the gene CST3, a “housekeeping” gene located on chromosome 20 (20p11.2). It was transcribed at a relatively stable level and expressed in all nucleated cells, and possessed several biologic functions, including regulating extracellular protein hydrolysis, modulating the immune system, and demonstrating antibacterial and antiviral activities [21]. Numerous studies have documented decreased CysC levels in tissues from various cancers, including breast cancer, prostate cancer, gastric cancer, uterine cancer, colon cancer, and non-small cell lung cancer [22,23,24,25]. This indicated that the expression of CysC in tissues was suppressed by tumorigenesis, and a decrease in CysC levels may trigger tumor formation, invasion, and metastasis. Furthermore, serum CysC was regarded as a tumor suppressor [26]. In contrast to the reduced CysC levels in cancer tissues, serum CysC levels in patients were elevated, which was correlated with a poorer prognosis [27, 28]. This phenomenon implied that low serum CysC levels might serve as a favorable prognostic biomarker for RCC patients, although its precise mechanism remained unclear. We hypothesized that this phenomenon may be closely associated with the increased levels of cysteine proteases and the decreased renal function in cancer patients.

Furthermore, an increase in serum CysC levels in RCC may signify heightened levels and activity of extracellular proteases within tumor or stromal host cells, thereby which indirectly reflected the tumor's malignant potential and its destructive capabilities [29]. As the primary substrate of CysC, the enzymatic activity of cysteine protease frequently became dysregulated during tumor transformation [30, 31]. Within the tumor microenvironment, the elevated and aberrant localization of protease activity played a pivotal role in cancer progression, proliferation, invasion, and metastasis [32]. Some studies indicated that the levels of protease D activity in both tissue and urine samples from RCC patients surpassed those found in healthy individuals, but the serum levels and activity of protease D in RCC patients remained comparable to those of healthy individuals [33, 34]. Despite the ongoing debate regarding changes in protease expression in RCC, it was indisputable that the balance between CysC and its cysteine protease substrates was of considerable significance.

Evaluating renal function in RCC patients was crucial as renal dysfunction was directly associated with a higher mortality rate following a cancer diagnosis [35]. Some studies indicated that postoperative decline in renal function among RCC patients [36, 37] although the underlying mechanism remained unclear, may be linked to the development of chronic kidney disease in cancer patients [38]. Previous research has identified CysC as a significant biomarker for assessing renal function [39]. Compared to biomarkers such as SCr, eGFR, and BUN, CysC was not unaffected by diet, nutrition, and muscle mass. One included study confirmed that RCC patients with elevated preoperative serum Cys C levels were more likely to experience increased creatinine levels and decreased renal function. Due to the diverse cellular processes of CysC within the tumor microenvironment, there was controversy regarding its application in oncology practice among scholars. Another included study demonstrated a strong positive correlation between BUN/SCr and CysC. Integrating these two factors could provide more accurate prognostic information for postoperative RCC patients although this required further validation through high-quality clinical trials. While the significance of serum Cys C in assessing renal function for RCC patients still required further investigation, it continued to serve as a reliable predictor of RCC prognosis.

One study has indicated that when the postoperative CysC level increased by 0.9–1.0 mg/l, the postoperative creatinine level stabilized at approximately 1.3 mg/dl, while when the postoperative CysC level was either below 0.9 mg/l or above 1.0 mg/l, CysC and creatinine levels remained highly correlated [40]. The author described the postoperative plateau period, characterized by creatinine levels ranging from 1.2 to 1.3 mg/dl, as the “creatinine blind area”, fluctuations in CysC levels may serve as more accurate indicators of renal function impairment during this area. In the “creatinine blind area”, up to one-third of patients may not exhibit detectable postoperative renal function impairment, but significant changes in serum CysC levels can still be observed in these patients within this area. This suggested that CysC may become a more effective indicator for assessing renal function in patients with creatinine blind spots, allowing for more accurate evaluation of renal function in RCC patients and assisting in the decisions of prognosis and treatment.

It was worth emphasizing that predetermined cut-off ratios for Cys C in predicting tumor prognosis may vary based on tumor stage, which was related to the malignant degree of tumors, as well as factors, such as sample sizes, survival endpoints, and follow-up times. One included study analyzed the relationship between serum Cys C levels and OS and DFS in patients at different stages, including pTNM-stage, pT-stage, pN-stage, and pM-stage. The study demonstrated that low preoperative serum Cys C levels were a favorable prognostic factor for OS in patients at pT1-2, pN0, and pM0 stages, as well as for DFS in pT1-2 and pN0 stages. Bodnar et al. reported that compared with patients with localized RCC, serum CysC level in patients with metastatic RCC has not significantly changed, but there were few relevant studies, and more high-quality clinical trials were still needed to prove this finding [17].

While meta-analysis revealed a strong correlation between serum CysC levels and RCC, several limitations must be recognized. For example, all included studies were retrospective, which increased the potential for bias. Second, changes in dietary habits, underlying diseases, medications, and lifestyle factors may affect blood-based markers, potentially introducing bias. Third, no predetermined cut-off ratios for blood-based markers were identified in this study. Lastly, since the majority of individuals in our research were from the Asian region, extrapolating the results may be challenging.