Adenovirus is one of the most commonly used vectors for gene therapy and it is the first
approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected
cells, but it can also engage the immune system, promoting activation and maturation of antigen-
presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory
actions result in a “personalized in situ vaccine” for each patient. In order to take full advantage of
these features, we should try to understand how adenovirus interacts with the immune system, what
are the receptors involved in triggering subsequent signals and which kind of responses they elicit.
Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune
responses for enhancement of anti-tumor efficacy.
In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system
and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)-
like receptors and other immune sensors. Then we describe the effect of these interactions on the
adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the
most significant preclinical and clinical results in the field of gene therapy where researchers have
engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators.