Why do some tumors fail to respond to immune checkpoint blockade (ICB) therapy? New research by the Spranger Lab, in collaboration with the Love and Wittrup Labs, suggests that non-responsive T cells may be dysfunctional due to differences in cytokine signaling during T cell activation in the tumor-draining lymph node. Their findings, published in Science Immunology, suggest that cytokine therapy could improve the tumors' response to ICB.