Two commonly used chemotherapeutic agents, gemcitabine and 5-fluorouracil, have been found to be implicit in their own inefficacy. They both activate the NOD-like receptor family and the pyrine domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (the inflammasome) via the release of cathepsin B from lysosomes. Inflammasome activation results in the secretion of IL-1β and, subsequently, IL-17 release by CD4+ T cells. The study, conducted in myeloid-derived suppressor cells, demonstrated that these events limited the activity of the chemotherapy. Furthermore, thymoma-bearing mice without key inflammasome components (Nlrp3−/−, Casp1−/− or those treated with IL-receptor antagonists) responded better to chemotherapy than those with intact inflammasomes. These results suggest that challenge with gemcitabine or 5-fluorouracil could be combined with IL-1 inhibition to improve response.