Oncolytic virus therapy is based on the ability of viruses to effectively infect and kill tumor cells without destroying the normal tissues. While some viruses seem to have a natural preference for tumor cells, most viruses require the modification of their tropism to specifically enter and replicate in such cells. This review aims to describe the transductional targeting strategies currently employed to specifically redirect viruses towards surface receptors on tumor cells. Three major strategies can be distinguished; they involve (i) the incorporation of new targeting specificity into a viral surface protein, (ii) the incorporation of a scaffold into a viral surface protein to allow the attachment of targeting moieties, and (iii) the use of bispecific adapters to mediate targeting of a virus to a specified moiety on a tumor cell. Of each strategy key features, advantages and limitations are discussed and examples are given. Because of their potential to cause sustained, multiround infection—a desirable characteristic for eradicating tumors—particular attention is given to viruses engineered to become self-targeted by the genomic expression of a bispecific adapter protein. 1. Introduction Cancer is one of the major health problems of our times. Though the prognosis for people diagnosed with, at least some forms of, cancer has increased considerably, it is more typical a disease of which treatment is initially effective, to be followed later by an irreversible and eventually fatal relapse. Already for decades, cancer treatment is based on three types of approaches: surgery, radio-, and chemotherapy. While the scientific and technological advancements have improved the efficacy of each of these classical approaches tremendously, and while also some new therapies have evolved including immunotherapy, the treatments apparently fail to eradicate all residual tumor cells or metastases completely. Therefore, additional means are urgently required to support or replace the conventional therapies. Hence, a variety of new approaches is currently being explored, one of which is based on the use of viruses. Oncolytic viruses are defined by their ability to specifically kill tumor cells, but to leave the normal tissues unharmed. Their most characteristic features, thus, are their target specificity and their cytolytic capacity. Ideally, they exhibit additional features including, but not limited to, a high reproductive capacity in vivo, the ability to recruit uninfected neighboring cells (syncytia formation), the ability to infect both dividing and nondividing
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