Activation of endogenous retroviruses in tumor cells and their immunomodulatory mechanisms: from molecular basis to clinical translation

Endogenous retroviruses (ERVs), regarded as “molecular fossils” embedded within the human genome, have been shown to exhibit increasingly intimate associations with tumor initiation, progression, and immune evasion through aberrant activation events. This review aims to systematically dissect the molecular mechanisms underlying ERV reactivation in the tumor microenvironment (TME), which are mediated by epigenetic reprogramming, transcription factor network dysregulation, and genomic instability, while highlighting their dual role in immune modulation. On one hand, ERVs activate innate and adaptive antitumor immunity via “viral mimicry” responses; on the other hand, they can induce the expression of immune checkpoint molecules and foster an immunosuppressive TME, thereby facilitating tumor immune evasion. Leveraging recent advancements in single-cell multi-omics and spatial transcriptomics technologies, this review delineates the dynamic expression patterns of ERVs in tumor heterogeneity and integrates extensive preclinical and clinical trial data to illustrate the translational potential of ERV-targeted strategies in tumor diagnosis, prognostic assessment, and immunotherapy. Finally, this review proposes addressing current research bottlenecks by harnessing spatiotemporally precise gene-editing technologies and AI-driven ERV activity prediction models, thus offering a novel paradigm for the development of next-generation tumor immunotherapies.