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Simple Summary: Enteroviruses are considered to be promising oncolytic agents towards a variety of human cancers. Enteroviruses comprise polioviruses, coxsackieviruses, and echoviruses. Their efficacy depends on their ability to infect respective tumor cells. As non-enveloped viruses, they can enter cells via different receptors, many of which are expressed in tumors at higher levels. However, understanding the precise role of individual receptors in virus entry is complicated, and often requires the development of knockdown/knockout models. In this review we summarize current concepts about the roles of individual receptors in the entry of enteroviruses into cells, as well as the impact of host RNA-sensing machinery that can activate interferon signaling in response to viral infections. Several other host cell factors are also discussed. Enteroviruses, with their diverse clinical manifestations ranging from mild or asymptomatic infections to severe diseases such as poliomyelitis and viral myocarditis, present a public health threat. However, they can also be used as oncolytic agents. This review shows the intricate relationship between enteroviruses and host cell factors. Enteroviruses utilize specific receptors and coreceptors for cell entry that are critical for infection and subsequent viral replication. These receptors, many of which are glycoproteins, facilitate virus binding, capsid destabilization, and internalization into cells, and their expression defines virus tropism towards various types of cells. Since enteroviruses can exploit different receptors, they have high oncolytic potential for personalized cancer therapy, as exemplified by the antitumor activity of certain enterovirus strains including the bioselected non-pathogenic Echovirus type 7/Rigvir, approved for melanoma treatment. Dissecting the roles of individual receptors in the entry of enteroviruses can provide valuable insights into their potential in cancer therapy. This review discusses the application of gene-targeting techniques such as CRISPR/Cas9 technology to investigate the impact of the loss of a particular receptor on the attachment of the virus and its subsequent internalization. It also summarizes the data on their expression in various types of cancer. By understanding how enteroviruses interact with specific cellular receptors, researchers can develop more effective regimens of treatment, offering hope for more targeted and efficient therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncolytic viruses infect tumor cells and trigger their death and elimination by the immune system. Several viral strains have been introduced into clinical practice. However, their therapeutic efficacy remains controversial. Here, we show that Coxsackievirus B5 (CVB5) causes the death of glioblastoma cells. Interestingly, 2-deoxyglucose, an inhibitor of glycolysis augments the oncolytic effect induced by CVB5. This synergism occurs in cells with a high respiratory phenotype and increased glycolytic capacity. Thus, 2-deoxyglucose or its analogs can be evaluated further as drugs to potentiate the oncolytic effects of enteroviruses against glioblastoma multiforme. Glioblastoma multiforme (GBM) is one of the most common types of brain tumor. Despite intensive research, patients with GBM have a poor prognosis due to a very high rate of relapse and significant side effects of the treatment, with a median survival of 14.6 months. Oncolytic viruses are considered a promising strategy to eliminate GBM and other types of cancer, and several viruses have already been introduced into clinical practice. However, identification of the factors that underly the sensitivity of tumor species to oncolytic viruses or that modulate their clinical efficacy remains an important target. Here, we show that Coxsackievirus B5 (CVB5) demonstrates high oncolytic potential towards GBM primary cell species and cell lines. Moreover, 2-deoxyglucose (2DG), an inhibitor of glycolysis, potentiates the cytopathic effects of CVB5 in most of the cancer cell lines tested. The cells in which the inhibition of glycolysis enhanced oncolysis are characterized by high mitochondrial respiratory activity and glycolytic capacity, as determined by Seahorse analysis. Thus, 2-deoxyglucose and other analogs should be considered as adjuvants for oncolytic therapy of glioblastoma multiforme. [ABSTRACT FROM AUTHOR]