Combination Therapy Approaches to Enhance the Efficacy of ERV-Targeting Vaccines in Cancer

Abstract

Endogenous retroviruses (ERV) are the genetic remnants of retroviruses in which proviral sequences integrated into germline cells of our ancestors. Although the vast majority of ERV sequences have accumulated mutations over the course of human evolution, some still contain open reading frames encoding full-length retroviral proteins. These sequences are typically epigenetically silenced in healthy adult human tissues. However, epigenetic dysregulation in cancer results in aberrant expression of ERVs in multiple cancer types. Therefore, ERVs represent a class of attractive therapeutic targets in cancer due to their immunogenicity and high expression in cancer cells compared with healthy tissues. In this review, we summarize the roles of ERVs in cancer and their immunogenicity, highlight the most recent advances in ERV-targeting strategies, discuss their challenges, and examine potential combination approaches that could further enhance the antitumor efficacy of ERV-targeting vaccines.

Figure 1.

Maintenance of endogenized viral genomes. A, An intact ERV sequence is composed of gag, pro, pol, and env genes flanked by two LTRs. The vast majority of proviral genomes are highly fragmented and do not encode full-length proteins. However, a small number of proviral genomes are still able to encode full-length proteins following selective pressure. B, ERVs are classified into three classes, class I (γ-like), class II (β-like), and class III (spuma-like; refs. –4). Panel A image modified from previous literature (Song et al., ref. , reprinted with permission from Springer Nature). Created with BioRender.com. Maldonado Montalban, M. (2025) https://BioRender.com/c47u762.

Figure 2.

ERV proteins with essential roles during human embryogenesis. Image modified from previous literature (Reprinted Wang et al., ref. , © 2024, with permission from Elsevier; used with permission of Springer Nature BV from Dopkins et al., ref. , © 2024, permission conveyed through Copyright Clearance Center, Inc.). Created with BioRender.com. Maldonado Montalban, M. (2025) https://BioRender.com/r46z436.

Figure 3.

The ISD within the retroviral ENV protein is conserved among ERVs from different species, as seen in murine leukemia virus (MLV), feline leukemia virus (FLV), and human ERVs, such as HERV-E clone 4-1. Expression of the retroviral ENV protein increases immunosuppression by inhibiting lymphocyte proliferation and decreasing activation of monocytes, T cells, and NK cells that could further contribute to tumor progression. Image modified from previous literature (Cianciolo et al., ref. . Reprinted with permission from American Association for the Advancement of Science). Created with BioRender.com. Maldonado Montalban, M. (2025) https://BioRender.com/w77o051.

Figure 4.

Potential combination approaches with therapeutic ERV cancer vaccines for targeting highly expressing ERV tumors. A, Vaccination with ERV-targeted vaccines using adenoviral vectors induces the expression of ERVs in antigen-presenting cells (APC), which in turn present the tumor antigen to CD8⁺ T cells and CD4⁺ T cells through MHC class I and MHC class II, respectively. B, ICIs such as anti–PD-1 further expand ERV-specific CD8 T cells by reducing immunosuppression in the TME. C, The use of additional immuno-oncology agents such as N803 could further enhance antitumor immunity by increasing T-cell and NK-cell activation. The presence of ERV antibodies in the TME could further promote antibody-dependent cytotoxicity by NK cells. D, Treatment with epigenetic modifiers, such as Aza, could further increase tumor cell visibility to immune surveillance by upregulating the expression of ERVs in tumor cells and promoting viral mimicry. Increased transcription of ERV double-stranded RNA (dsRNA) transcripts could trigger type 1 interferon responses and promote JAK/STAT signaling and activation of interferon-stimulated genes (ISGs), further increasing HLA expression in tumor cells. Created with BioRender.com. Maldonado Montalban, M. (2025) https://BioRender.com/i66w154.