**6. Conclusions**

While our understanding of how to capture the full potential of oncolytic virotherapy continues to evolve, it appears clear that release of tumor associated antigens and activation of the immune system is crucial for these anti-oncolytic agents. Consequently, combinations of oncolytic viruses with immune checkpoint inhibitors are dominating the current clinical trial landscape [295,296]. However, combinations with select small molecule compounds can address some of the limitations of the oncolytic core features and improve oncolysis, intra-tumoral spread, immunogenicity of tumor cell killing, as well as improving antigen processing and the regulation of immune cell populations. Such combinations have now also entered clinical testing [18] (for currently active trials, see Table 3).

In conclusion, there are many potent compounds available to counter most immunosuppressive mechanisms a tumor can display. The big challenge will be to develop methods to efficiently and affordably determine which combination to use when, and for which patients.

**Author Contributions:** Conceptualization, B.S. and G.W.; writing–original draft preparation, B.S., K.A., J.P. and G.W.; writing–review and editing, B.S. and G.W.; visualization, B.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** B.S., K.A. and G.W. were supported by funding from the Christian Doppler Research Association.

**Conflicts of Interest:** B.S. and J.P. are employees of ViraTherapeutics GmbH and Boehringer Ingelheim Pharma, respectively. G.W. serves as scientific advisor for Boehringer Ingelheim. ViraTherapeutics or Boehringer Ingelheim had no role in the conceptualization or writing of the manuscript. The other authors declare no competing interest.
