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Background Clear cell renal cell carcinoma (ccRCC) is the most common and lethal form of kidney cancer. Despite therapeutic advances such as VEGF inhibitors, immune checkpoint inhibitors (ICIs) and a recently approved HIF2 inhibitor, most patients with metastatic ccRCC eventually relapse, and survival rates remain below 50%. While ccRCC is immunogenic—characterized by high T cell infiltration and occasional spontaneous tumor regression—the underlying antigenic drivers are largely unknown. Loss of the VHL gene, a hallmark of ccRCC, leads to stabilization of HIF2, a key oncogenic transcription factor. In one patient who achieved complete remission following allogeneic stem cell transplantation (allo-SCT), donor T cells recognized a HIF2-induced endogenous retrovirus (ERV), ERVE-4. Given that ERVs constitute approximately 8% of the human genome, we investigated whether additional HIF2-regulated ERVs contribute to ccRCC immunogenicity.Methods We employed a multi-omics approach to determine whether ERVs in ccRCC are transcribed, translated, and presented by HLA complexes. RNA-seq, ChIP-seq, PRO-seq, and single-cell RNA/ATAC-seq profiled ERV transcription and regulatory mechanisms. Targeted long-read DNA sequencing enabled precise resolution of sequence variants in homologous ERV loci, which is critical for accurate open reading frame (ORF) prediction and construction of mass spectrometry (MS) search databases. Polysome-seq identified ERV transcripts undergoing active translation, while HLA immunoprecipitation—either endogenous or via tagged exogenous HLA—coupled with MS detected HLA-bound ERV-derived peptides. Immunogenicity was evaluated using IFNγ ELISpot assays in humanized mouse models and immune cells from ccRCC patients.Results Transcriptomic and immunopeptidomic analyses identified dozens of additional HIF2-induced ERVs that are relatively intact and presented as HLA-bound peptides in ccRCC but absent in matched normal tissues. These ERV-derived peptides were recognized by T cells from archived samples of ccRCC patients who responded to allo-SCT or ICI therapy, supporting their role in tumor immune recognition. To further characterize these ERVs, we applied targeted long-read sequencing to precisely map specific ERV loci, enabling accurate prediction of their ORFs. We integrated these sequence variants into downstream MS databases in a cell line-specific manner. Additionally, we overexpressed tagged prevalent HLA alleles in ccRCC cell lines to generate a reference database of ERV-derived, HLA-bound, peptides across common HLA types, facilitating systematic identification of these antigens.Conclusions This study demonstrates that HIF2α drives the expression of immunogenic, tumor-specific ERVs in ccRCC. These ERVs are translated, presented by HLA molecules across prevalent HLA alleles, are recognized by T cells, highlighting their potential as targets for next-generation immunotherapies.