In this study, among the 73 investigated plasma humoral factors, MMP1, IL-1β, sTNFR-1, and IL-6 were prognostic factors for both PFS and OS; higher expression of these factors was associated with worse PFS and OS. In addition, our multivariate analysis identified MMP1 and IL-6 as significant prognostic factors for PFS and OS, respectively.

MMP1 is an endopeptidase expressed in various cells such as fibroblasts, keratinocytes, endothelial cells, monocytes, and macrophages. The epithelial expression of MMP1 has been reported to inhibit mitochondrial function, increase HIF-1α expression, decrease the generation of reactive oxygen species, and contribute to proliferative, migratory, and antiapoptotic cell phenotypes [7]. MMP1 also mediates the invasion of circulating tumor cells into the tumor environment [8]. For example, MMP1 overexpression is associated with tumor invasion and metastasis and is involved in the pathogenesis of lung cancer [9]. In colorectal cancer, MMP1 promotes cancer cell growth by stimulating the cell cycle [10]. Notably, the expression of MMP1 is inversely associated with the infiltration of T cells and macrophages in cervical squamous cell carcinoma [11].

IL-6 is a multifaceted cytokine involved in various immune responses such as autoimmunity and antitumor immunity [12]. In the tumor immune microenvironment of RCC, IL-6 induces the expression of SOCS3 (suppressor of cytokine signaling-3), a negative regulator of cytokine signaling that promotes tumor cell invasion and metastasis. The inhibition of this cascade may prevent tumor cells from undergoing invasive metastasis and prolong prognosis [13]. Notably, IL-6 has also been reported as a prognostic predictor of ICI therapy in lung cancer and melanoma [14, 15]. In addition, combination therapy with ICIs and IL-6 inhibitors exhibits a decoupling effect on the antitumor effects and toxicity [16]. Moreover, CRP is a surrogate marker for IL-6 and has been reported to be a prognostic factor in previous reports, we also analyzed it in the present study; however, we observed no significant differences [6]. Given that IL-6 exhibited a considerably high HR for OS in our multivariate analysis, combination therapy with ICIs and anti-IL-6 antibodies may also prolong OS in patients with RCC.

IL-1β induces tumor angiogenesis through activation of the vascular endothelial growth factor pathway, increases immunosuppressive cells, and accelerates tumor invasion via secretion of GM-CSF and IL-6 [15] [17, 18]. IL-1β is also a prognostic factor in various cancers, including lung, breast, colon, gastric, and esophageal cancers [19] [20,21,22,23,24]. In RCC, IL-1β promotes the infiltration of myeloid-derived suppressor cells and tumor-associated macrophages and confers resistance to acquired and innate immunity. Thus, based on the results of this study, combination therapy with IL-1β inhibitors and ICIs may enhance antitumor effects in RCC [25].

In addition, sTNFR-1 inhibits the action of TNF-α by competitively preventing the binding of circulating TNF-α to the transmembrane form of TNFR-1. Because TNFα is a pleiotropic cytokine with several immunological roles [26], the inhibition of TNFα mediated by sTNFR-1 may suppress the antitumor activity of ICIs in patients with RCC.

High expression of MMP1 is a predictor of irAEs; high MMP1 expression is highly associated with irAEs in lung cancer [27]. The comprehensive exploration of the relationship between MMP1 and irAE is challenging. However, it is plausible that the involvement of MMP1 with monocytes may contribute to irAEs. High MMP1 expression may also indicate an elevated expression state of TNFα, GM-CSF, and IFN-γ [28, 29]. This collective upregulation of all these factors may be responsible for the complex activation of the immune response in vivo and the subsequent irAE induction following ICI administration, warranting future comprehensive investigations.

Notably, in the present study, the subgroup analysis demonstrated that the prognostic roles of each soluble factor may be different between the patients treated with ICIs with and without ipilimumab. In patients treated with both nivolumab and ipilimumab, IL-1β and sTNFR-1 were not significant prognostic factors for PFS or OS, suggesting that ipilimumab may be involved in tumor immunity by regulating the activity of IL-1β and sTNFR-1. The relationship between CTLA4 and IL-1β/sTNFR-1 remains unclear. However, IL-1β secretion is regulated by CTLA4-Ig fusion protein [30], and the administration of IL-1β inhibitors in a mouse model of hepatitis upregulates the expression of PD-1 and CTLA4 in the liver [31]. Moreover, TNFR-1 contributes to the termination of immune responses through its ability to induce apoptosis, and the possible involvement of CTLA4 in these apoptotic pathways has also been reported [32]. Given that CTLA4 inhibition may lead to apoptosis more readily in groups overexpressing IL-1β and sTNFR-1, combined treatment with nivolumab and ipilimumab may be recommended in patients with high IL-1β and sTNFR-1 expression levels in the plasma. However, these recommendations are speculative and require further experimentation and case series.

This study has several limitations. First, it was a single-center retrospective study with a limited number of patients and a short observation period. Second, the treatment lines and regimens used varied. Finally, patients with tumor types other than clear cell carcinoma were included in this study. Further studies with a larger number of patients on the same treatment lines and regimens are needed to investigate the prognostic roles of each factor more accurately.

In summary, this study demonstrated that MMP1, IL-1β, sTNFR-1, and IL-6 are prognostic factors in patients with RCC treated with ICIs. In particular, IL-6 was detected as an independent predictor of OS, and MMP1 was identified as an independent predictor of PFS in the multivariate analysis.