Malignant renal tumors are one of the most common cancers worldwide, with a high incidence in men and the elderly [1]. Renal cell carcinoma (RCC) accounts for approximately 80% of malignant renal tumors, and clear cell RCC (ccRCC), a highly invasive and heterogeneous tumor, is the most common histological subtype of RCC [2]. Currently, one of the main RCC treatments is local tumor resection. However, metastasis is identified in approximately 30% of patients with RCC at the first visit [3], and approximately 40% of patients develop recurrence and metastasis following primary tumor resection [4]. Therefore, the early diagnosis of ccRCC is crucial for improving prognosis. Moreover, novel biomarkers need to be identified that can be used to diagnose and predict patient prognosis.

Immune checkpoints are a group of cell surface proteins that control the initiation, duration, and intensity of the immune response via activation or inhibition signaling [5]. Immune checkpoint inhibitors prevent T cell death, reduce damage to healthy tissues, and maintain self-tolerance and homeostasis. In cancer, immune checkpoint inhibitors contribute to the immune escape of cancer cells. Thus, they are usually considered biomarkers of cancer [6]. Immune regulatory ligands belonging to the B7 family regulate the activation and differentiation of T cells and interact extensively with the CD28 superfamily, the members of which are widely expressed in immune cells and various cancer tissues, contributing to cancer immune evasion [7]. CD276 (B7 homolog 3 protein) is an important immune checkpoint member of the B7 and CD28 families and plays a critical role in inhibiting T cell function. It is highly overexpressed in many solid cancers in humans and is usually closely correlated with poor prognosis of patients [8].

The number of studies on the molecular mechanism of CD276 is steadily increasing. CD276 was reported to promote the activity of various tumors in vivo and in vitro and enhance their proliferation, migration, invasion, and chemotherapy resistance [9]. Furthermore, CD276 downregulation reduced the proliferation of colorectal cancer (CRC) cells, whereas CD276 overexpression significantly promoted CRC cell proliferation and migration [10,11]. Additionally, CD276 silencing reduced the proliferation, invasion, and migration of the A549 lung adenocarcinoma cell line [12]. Epithelial–mesenchymal transition (EMT) is a key step in cancer metastasis, and CD276 downregulation inhibits the EMT of lung adenocarcinoma cells [12]. CD276 also promotes the EMT of hepatocellular carcinoma through the JAK2/STAT3/Slug signaling pathway [13]. In non-small cell lung cancer cells, CD276 upregulates SIRT1 expression to further promote EMT through the PI3K/AKT signaling pathway [14]. The functions of CD276 in ccRCC have already been reported. For instance, CD276 is highly expressed in the vascular endothelium of ccRCC and is correlated with ccRCC staging and tumor-node-metastasis classification [15]. Furthermore, CD276 expression is related to the poor prognosis of patients with ccRCC, and CD276 knockdown affects the expression of tumor metastasis-related genes and significantly inhibits ccRCC metastasis [16]. It was also reported that high levels of CD276 expression were not only related to a variety of clinically adverse and pathological features but also significantly associated with an increased risk of mortality in ccRCC [17]. The above-mentioned studies demonstrate that CD276 differential expression has important prognostic value for ccRCC. However, the regulatory pathway of CD276 in ccRCC requires thorough study, and drugs targeting CD276 also need further exploration.

In this study, we evaluated CD276 expression levels in cancer tissues and adjacent normal tissues derived from patients with ccRCC and assessed the influence of CD276 on patient prognosis. Briefly, we analyzed the relationship between CD276 expression and the biological function of cells, followed by an analysis of the protein—protein interaction (PPI) network and functional enrichment analysis of CD276. We also assessed immune infiltration and drug analysis and experimentally confirmed high levels of CD276 expression in ccRCC cell lines. Our study findings may help to identify a novel biomarker and provide a new perspective for ccRCC diagnosis and treatment.