New therapies that promote antitumor immunity have been recently developed. Most of these immunomodulatory approaches have focused on enhancing T-cell responses. Although these therapies have led to unprecedented successes, only a minority of cancer patients benefit from them, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for long-lasting, multilayered tumor control. We will present innovative anti-tumor therapies based on the manipulation of the innate immune system. In addition, given the urgent need for effective treatments for pneumonia in patients with COVID-19, the elucidation of the immune responses that occur during the course of COVID-19 could lead to the repurposing of approved immunomodulatory drugs and candidate drugs that have already been tested in clinical trials. Along this line, we will present our results indicating the association of COVID-19 inflammation with activation of the C5a–C5aR1 axis.