Nectin-4 drives aggressive tumor biology and poor prognosis in renal cell carcinoma.

Nectin‑4, a cell adhesion molecule and emerging therapeutic target in several malignancies, has not been fully characterized in renal cell carcinoma (RCC). This study aimed to define the clinical significance, biological function, and therapeutic implications of Nectin‑4 across RCC subtypes. Immunohistochemistry of 273 primary RCC samples revealed that the expression of Nectin‑4, although present in a minority of clear cell RCC (ccRCC) cases, was significantly enriched in nonclear cell RCC (nccRCC). Nectin‑4 positivity was correlated with adverse pathological features, including higher pT stage, tumor grade, and venous invasion. In ccRCC, the expression of Nectin‑4 was associated with inferior overall survival, consistent with the findings from a public dataset analysis. In vitro experiments demonstrated that Nectin‑4 overexpression enhanced the proliferation and invasion of multiple RCC cell lines, supporting a tumor‑promoting role. Transcriptomic analyses across TCGA‑KIRC, TCGA‑KIRP, JAVELIN Renal 101, and CheckMate‑025 cohorts showed that the high expression of NECTIN4 was strongly associated with epithelial-mesenchymal transition, inflammatory signaling, sarcomatoid features, and genomic dedifferentiation. Despite these aggressive biological features, the expression of NECTIN4 was not correlated with immune infiltration markers and did not predict the clinical benefit of immune checkpoint inhibitors. These findings suggest that Nectin‑4 is a marker of tumor aggressiveness and dedifferentiation, rather than an immunotherapy biomarker. Given its relatively high expression in nccRCC and its functional contribution to malignant behavior, Nectin‑4-directed antibody-drug conjugates may represent a promising therapeutic option for this underserved population and warrant further investigation.