Circulating ERVFRD-1 and MFSD2A Are Associated with Immunotherapy Response in Metastatic Clear Cell Renal Cell Carcinoma

<b>Background/Objectives</b>: Immune checkpoint inhibitor (ICI)-based combinations have significantly improved outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, a substantial number of patients fail to derive clinical benefit, highlighting the need for reliable predictive biomarkers. Circulating biomarkers represent an attractive, non-invasive alternative to tissue-based assays. This study aimed to evaluate the immunity-related genes <i>ERVFRD-1</i> and <i>MFSD2A</i> as potential blood-based candidate biomarkers associated with response to ICI-based therapy in mccRCC. <b>Methods</b>: Peripheral blood samples were collected prior to treatment initiation from 34 patients with mccRCC receiving PD-1-based therapy. Gene expression levels of <i>ERVFRD-1</i> and <i>MFSD2A</i> were quantified using real-time PCR. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral blood samples from healthy individuals were included as controls. <b>Results</b>: Both <i>ERVFRD-1</i> and <i>MFSD2A</i> were significantly dysregulated in mccRCC patients compared with healthy controls. Their expression differed between patients with clinical benefit and those with progressive disease. Specifically, patients with progressive disease exhibited reduced <i>ERVFRD-1</i> expression and increased <i>MFSD2A</i> expression compared with patients showing clinical benefit. <b>Conclusions</b>: <i>ERVFRD-1</i> and <i>MFSD2A</i> were associated with treatment response in this pilot cohort and may represent promising blood-based biomarker candidates, requiring validation in larger prospective multicenter studies.