*Review* **Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits**

**Bart Spiesschaert 1,2,3,4, Katharina Angerer 1,2, John Park <sup>4</sup> and Guido Wollmann 1,2,\***


**Simple Summary:** Oncolytic viruses can be a potent tool in the fight against cancer. However, in clinical settings their ability to replicate in and kill tumors is often limited. Combinations with specific small molecule compounds can address some of these limitations and help oncolytic viruses reach their full potential. The aim of this review is to provide an overview of the different types of small molecules with which oncolytic viruses can achieve therapeutic synergy. We focus on the underlying mechanisms in three functional areas: combinations that increase viral replication, enhance tumor cell killing and improve antitumor immune responses.

**Abstract:** The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

**Keywords:** oncolytic virus; small molecule; cancer immune therapy; combination therapy; cancer therapy; immunotherapy
