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Background Human Endogenous Retroviruses (HERVs) are remnants of ancient viral infections that have become permanently integrated into the human genome. Among them, HERV-K stands out due to its aberrant reactivation in solid tumors while remaining silent in healthy tissues, positioning it as a compelling cancer antigen. Elevated HERV-K levels have been linked to poor clinical outcomes, underscoring its relevance in tumor progression. Furthermore, HERV-K is upregulated during aging and cellular senescence—two biological processes increasingly implicated in cancer development. These findings highlight HERV-K as a promising target for immunotherapeutic intervention. This study investigates the therapeutic potential of re-engineered strategies to target HERV-K, aiming to exploit its tumor-restricted expression for precision oncology.Methods HERV-K expression was profiled in late-stage cancer patients across >40 cancer types using RNA-seq data. IPT001, a novel adenoviral vector platform to deliver virus-like particles (VLPs) encoding HERV-K proteins with a strategic immunostimulatory point mutation, was developed ( figure 1A). Immunogenicity was assessed in vitro in human PBMCs as well as in vivo in mice and non-human primates. HERV-K-specific T-cell recognition of tumor cells was evaluated in HLA-restricted assays. Therapeutic efficacy was tested in a HERV-K-expressing renal cell carcinoma (RENCA)-based murine tumor model, including a combination arm with anti-PD-1 checkpoint blockade.Results Transcriptomic analysis demonstrated consistent upregulation of HERV-K across multiple solid tumor types, reinforcing its role as a cancer antigen. In ex vivo human PBMC cultures, the therapeutic candidate IPT001 effectively primed and expanded CD8+ and CD4+ T-cells specific for HERV-K. These T-cells exhibited functional activation upon co-culture with HLA-matched HERV-K-expressing cancer cell lines, confirming antigen specificity. In vivo, IPT001 elicited strong HERV-K-specific cellular and humoral immune responses in murine models. In the RENCA tumor model, IPT001 treatment significantly reduced tumor burden. Expanding on previous findings in a murine colorectal cancer model targeting murine ERVs alongside checkpoint blockade, combination of ITP001 with anti-PD-1 therapy yielded synergistic anti-tumor activity in the RENCA model. (figure 1B-1C).Conclusions This study establishes IPT001 as a promising immunotherapeutic targeting HERV-K, a previously undruggable cancer antigen. Through engineered immunostimulatory mutations, IPT001 overcame HERV-K´s intrinsic low immunogenicity, inducing potent cellular and humoral responses. The observed tumor regression and synergy with PD-1 blockade in preclinical models position HERV-K as a compelling cancer antigen with strong clinical translation potential. Future clinical studies are warranted to validate the efficacy of IPT001 as a monotherapy and in combination with standard-of-care treatments, including immune checkpoint inhibitors.Abstract 646 Figure 1