**4. Combinations Improving the Antitumor Immune Response**

Although initially envisioned to act primarily via their tumoricidal actions, over the last decade oncolytic viruses have emerged as potent immune activators and promising partners for cancer immunotherapies. The potential and promising preclinical and clinical findings of combinations of OVs with major immunotherapeutic approaches such as immune checkpoint inhibitors, T cell therapies, and cancer vaccines are beyond the scope of this small molecule themed review but are extensively discussed in recent publications [22,229–233]. Small molecule compounds that augment the antitumor immune response can modulate the tumor microenvironment or affect the adaptive immunity arm. The natural immune-activating characteristics renders OVs as the ideal platform to work in conjunction with small molecule immunotherapies. The TME consists of extracellular matrix (ECM), stromal and immune cells. Some of these cells such as Tregs, MDSCs and M2 macrophages drive an immunosuppressive environment by the secretion of cytokines such as IL-10 or TGF-β [234,235]. Within the TME many human tumors are infiltrated by Tregs [236], with preclinical data indicating that their depletion can enhance or restore antitumor immunity [237]. This makes Treg-depleting small molecules attractive candidates to counter cancer relapses caused by these immunosuppressive cells after OV treatment.
