MAVS is a double-edged sword.

It is well known that cancer cells can modulate expression of a variety of genes to gain an adaptive advantage. Many such changes affect the mitochondria, as altered metabolism and metabolic plasticity is one avenue through which cancers can enhance proliferation and survival.1Fendt S.M. Frezza C. Erez A. Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.Cancer Discov. 2020; 10: 1797-1807Crossref PubMed Scopus (88) Google Scholar Furthermore, cancer cells can also evade immune system responses for a survival advantage.2Seliger B. Strategies of tumor immune evasion.BioDrugs. 2005; 19: 347-354Crossref PubMed Scopus (115) Google Scholar Trishna et al. have discovered a functional role of mitochondrial antiviral signaling protein, MAVS, in multiple types of cancer, implicating MAVS as a common target in malignancies.3Trishna S. Lavon A. Shteinfer-Kuzmine A. Dafa-Berger A. Shoshan-Barmatz V. Overexpression of the mitochondrial anti-viral signaling protein, MAVS, in cancers is associated with cell survival and inflammation.Mol. Ther. Nucleic Acids. 2023; Abstract Full Text Full Text PDF Scopus (0) Google Scholar Additional findings show that MAVS binds to the voltage dependent anion channel 1 (VDAC1), which imply a stabilizing function of MAVS on mitochondria. MAVS depletion decreases cellular viability in tumors and decreases the nucleotide-binding and leucine-rich repeat containing family pyrin domain-containing-3 (NLRP3) and nuclear factor kappa B (NFkB) pathways in tumor cells. Finally, high levels of MAVS expression are correlated with poorer outcome in multiple human tumors. Given that the canonical function of MAVS in normal cells is to clear viral infection through activation of interferon α/β signaling, the role of MAVS in facilitating tumorigenesis is relatively unexpected. The old view of tumor cell metabolism is that tumors use aerobic glycolysis (referred to as the Warburg effect), and that this is the major form of cancer cell metabolism. More recent studies point to a more nuanced version of cancer cell metabolism, in which certain cancer cells can use both respiratory metabolism (for tumor growth) and glycolysis (for resistance to hypoxia, chemotherapy, and radiation).4Schiliro C. Firestein B.L. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation.Cells. 2021; 101056Crossref PubMed Scopus (123) Google Scholar,5Ganapathy-Kanniappan S. Geschwind J.-F.H. Tumor glycolysis as a target for cancer therapy: progress and prospects.Mol. Cancer. 2013; 12: 152Crossref PubMed Scopus (694) Google Scholar This plasticity allows tumors to rapidly relapse after therapy.1Fendt S.M. Frezza C. Erez A. Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.Cancer Discov. 2020; 10: 1797-1807Crossref PubMed Scopus (88) Google Scholar In order for tumor cells to undergo these changes, certain respiratory adaptations are required to allow tumor cells to effectively proliferate, using different substrates than normal cells.6Li S. Zeng H. Fan J. Wang F. Xu C. Li Y. Tu J. Nephew K.P. Long X. Glutamine metabolism in breast cancer and possible therapeutic targets.Biochem. Pharmacol. 2023; 210115464Crossref Scopus (0) Google Scholar It appears that MAVS, which is a cellular defense against viral infection, is being hijacked by tumor cells to stimulate both growth and immune evasion. Viral infection of normal cells induces a canonical signaling pathway, in which IRF3/7 signaling is activated, resulting in enhanced interferon α/β signaling, resulting in viral clearance. In tumors, constitutive MAVS signaling induces the NLPR3 inflammasome and NFkB activation, and depletion of MAVS using siRNA results in decreased viability. However, IRF3/7 signaling would make tumors more immunogenic and would be selected against in tumor evolution. Thus, one would predict that there is selective inactivation of IRF3 and 7 in carcinogenesis and perhaps immunosenescence. Studies have previously found using a temperature-sensitive large T antigen and oncogenic H-ras that loss of large T antigen signaling by temperature shift led to oncogene-induced senescence accompanied by decreased IRF7 signaling.7Costa A.D. Bonner M.Y. Rao S. Gilbert L. Sasaki M. Elsey J. MacKelfresh J. Arbiser J.L. Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells.Cancers. 2020; 12395Crossref Scopus (1) Google Scholar This mechanism could counteract the expected upregulation of IRF3 and 7. Second, in human papilloma virus-induced skin infections, in which keratinocytes assume senescent features, antigen presentation is impaired, and low levels of IRF7 are present, despite viral infection. IRF3 and 7 also have independent anti-senescent activity in other systems.8Le Poole C. Denman C.J. Arbiser J.L. Immunosuppression may be present within condyloma acuminata.J. Am. Acad. Dermatol. 2008; 59: 967-974Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Finally, in malignancies, IRF3 and 7 are often silenced, in part by hypermethylation, which supports their proposed role in cancer cell survival.9Wrangle J. Wang W. Koch A. Easwaran H. Mohammad H.P. Vendetti F. Vancriekinge W. Demeyer T. Du Z. Parsana P. et al.Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine.Oncotarget. 2013; 4: 2067-2079Crossref PubMed Google Scholar The figure below demonstrates a mechanism on how co-opting an antiviral defense can result in an advantage to cancer (Figure 1). In normal cells, viral infection leads to induction of a canonical antiviral defense, resulting in inhibition of viral replication and increased interferon α/β signaling. In chronic infection, senescence, and cancer, the same responses are chronically activated but can lead to immune evasion by downregulation of IRF3 and 7 signaling. The specific interaction between VDAC1 and MAVS could indicate a novel target for cancer therapy. It will be of interest whether future molecules that disrupt this interaction lead to decreased tumor growth in vivo by altering respiratory tumor metabolism. Finally, these molecules, in combination with hypomethylating agents, could lead to enhanced immune clearance if these agents induce IRF3 and 7. In addition, given how some genes can act as either an oncogene or tumor suppressor, given the metabolic preferences of different cancers, studying the impact of MAVS expression on metabolism across additional cancer lines could yield interesting results.10Alhazzazi T.Y. Kamarajan P. Verdin E. Kapila Y.L. SIRT3 and cancer: tumor promoter or suppressor?.Biochim. Biophys. Acta. 2011; 1816: 80-88Crossref PubMed Scopus (150) Google Scholar We have no conflicts of interest to declare.