These endogenous retrovirus (ERV) sequences usually do not contribute to the development of diseases, and most of them are considered "junk DNA". However, some of them play important functional roles. For example, syncytin is a protein essential for placental formation [1].
In addition, endogenous retroviruses have been found to exert a remarkable regulatory effect on stem cells. One of these viruses, named HERV-H (Human Endogenous Retrovirus-H), is believed in the academic community to have infected human ancestors approximately 25 million years ago and may be a key factor determining the pluripotency of human embryonic stem (ES) cells. It is preferentially expressed in human ES cells; when the RNA expression level of HERV-H decreases in ES cells, the morphology of these cells transforms into a fibroblast-like phenotype [2]. Such research findings indicate that endogenous retroviruses are indispensable for maintaining the pluripotency of human stem cells.
Earlier, a research team from the Sanford Burnham Prebys Medical Discovery Institute (SBP) published a study titled "FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells" in the journal Cell. This study proposed the viral-mimicry response mechanism, which utilizes the activation of endogenous retroviruses to "deceive" the human body and trigger instructions for initiating an immune response against tumor cells.
In another research direction, scholars have found in studies on various types of cancer that mutations in isocitrate dehydrogenase (IDH) are a common oncogenic mutation. Under normal conditions, the metabolite (α-ketoglutarate) produced by IDH provides energy for cellular metabolism. However, after IDH mutation, the metabolite produced is an oncogenic metabolite: 2-hydroxyglutarate (2HG). This metabolite does not participate in major metabolic processes but accumulates continuously in cells until the entire metabolic physiological process is disrupted, thereby promoting tumor growth.
Recently, research teams from institutions including Massachusetts General Hospital and the Broad Institute, in their studies on IDH1 inhibitors, discovered that these inhibitors also utilize the viral-mimicry response mechanism to enable the human body to initiate an immune response against cancer cells.
In the presence of an IDH1 inhibitor, DNA demethylation occurs in tumor cells, leading to the activation of endogenous retroviruses (ERVs). The activation of ERVs results in the accumulation of double-stranded DNA; under this condition, cyclic GMP-AMP synthase (cGAS), which was previously silenced, is reactivated. Subsequently, cGAS activates the stimulator of interferon genes (STING) signaling pathway and initiates the production of type I interferons (IFNs) involved in antiviral responses. In addition, IDH1 inhibitors can enhance the sensitivity of tumor cells to interferon-γ (IFN-γ), thereby achieving a more effective anti-cancer strategy.
Schematic Diagram of the IDH1 Inhibitor Mechanism [4]
A variety of drugs developed based on this viral-mimicry response mechanism for anti-cancer therapy have been marketed. Among them, the majority of clinical research pipelines for IDH1-targeted therapies have entered Phase 2-3 trials.
In the field of targeted drugs, nanobodies, as a new generation of targeted carriers, also possess irreplaceable research and development potential. Their targeting ability and biological activity may be combined with the viral-mimicry response mechanism to form a new anti-cancer strategy, achieving better therapeutic effects.
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