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

Background/Objectives: 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 ERVFRD-1 and MFSD2A as potential blood-based candidate biomarkers associated with response to ICI-based therapy in mccRCC. Methods: Peripheral blood samples were collected prior to treatment initiation from 34 patients with mccRCC receiving PD-1-based therapy. Gene expression levels of ERVFRD-1 and MFSD2A 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. Results: Both ERVFRD-1 and MFSD2A 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 ERVFRD-1 expression and increased MFSD2A expression compared with patients showing clinical benefit. Conclusions: ERVFRD-1 and MFSD2A were associated with treatment response in this pilot cohort and may represent promising blood-based biomarker candidates, requiring validation in larger prospective multicenter studies.