Human neutrophils form neutrophil extracellular traps (NETs) following activation of CXCR1 and −2 receptors by chemokines secreted by tumor cells, including IL-8 and CXCL-1, −2, and −8 (top left). NETs shield tumor cells from the cytotoxic effects of anti-tumor immune cells—specifically NK cells and CD8+ T cells—which can result in increased tumor growth (top right). Blocking NET formation via pharmacological PAD4 inhibitors, DNAse-I, Pertussis-toxin (Ptx), or CXCR1 and −2 inhibitors allows tumor cell contact with cytotoxic immune cells. Teijeira et al. demonstrate NETosis blockade by PAD4 inhibition can increase the efficacy of anti-PD1 plus anti-CTLA4 immune checkpoint inhibitors—highlighting exciting potential for a new therapeutic strategy where NET blockade maximizes the effect of immunotherapy.