Oncolytic adenovirus research evolution: from cell-cycle checkpoints to immune checkpoints

•Oncolytic adenoviruses should not be attenuated viruses.•In a small subset of patients, treatment of tumors with oncolytic viruses leads to tumor regression.•The main barriers to oncolytic virotherapy are both the host and the tumor immune systems.•Virotherapy combined with immune checkpoint modulators represents a logic avenue of progress.

Oncolytic adenoviruses are modified to exploit the aberrant expression of proteins in cancer cells to obtain cancer-selective replication. Moreover, the natural tropism of oncolytic adenoviruses can be redirected to tumor cells. Clinical trials revealed that oncolytic viruses showed poor replication in the tumor that is due in part to the immune response against the virus. More recent data demonstrated that tumor infection might subvert the tumor immune system and lead to an anti-tumor immune response. In the next few years, combination of adenoviruses with immune checkpoint antibodies and other immune modulators will be tested in clinical trials.