Viruses are the most abundant microorganisms on earth, and it is estimated that there are at least 10 times more viruses than bacteria in the human microbiome [1]. Unlike bacteria, many viruses can permanently settle in a host cell, are minimally influenced by environmental changes, and can even be inherited when infecting germline cells. Many viruses have coevolved with host species for millions of years and have developed mechanisms to evade immune recognition and maintain an equilibrium state with the host immune system. Recent studies have shown that breaking this immune equilibrium can activate the host antiviral immune responses [2–6]. Current cancer immunotherapies targeting immune checkpoint molecules have limited efficacy in treatment of noninflamed tumors (so-called “cold” tumors) that show few infiltrating T cells. The absence of T-cell infiltration is largely caused by the lack of tumor antigens, antigen presentation, and/or abundance of immunosuppressive cells in the tumor microenvironment (TME) [7]. To convert immune “cold” tumors to inflamed “hot” tumors, a variety of different strategies are currently under investigation, including bispecific antibodies, chimeric antigen receptor (CAR) T cells, oncolytic viruses, and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) agonists [8, 9]. The high mutation loads in tumors often result in expression of mutation-associated neoantigens, which are recognized as foreign antigens to the host T cells. These neoantigens have been found to be associated with improved responses to immune checkpoint inhibitors (ICIs) [10]. Interestingly, when suppressed viral gene expression in a tumor is reactivated from the virome, they are similarly recognized as tumor neoantigens by host immune systems [6, 11]. These findings suggest that activating immune responses against viruses in the human virome might be an effective tool for cancer immunotherapies.
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