Categories news Publication in Cell Post author By Dr. Maarten Altelaar Post date November 6, 2020 Publication in Cell in collaboration with Peeper lab New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)g pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNg-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNg receptor-deficient tumor cells to CD8 T cell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy.