Inducing apoptosis has long been considered an important effector mechanism of many anti-cancer therapies. Yet, several studies have suggested that engaging apoptosis can have tumour-promoting effects. During apoptosis, mitochondrial outer membrane permeabilization can lead to caspase activation. However, caspase activity can have undesirable outcomes, such as DNA damage. In search of a better way to eliminate cancer cells, Giampazolias et al. demonstrated that under caspase-deficient conditions, mitochondrial outer membrane permeabilization can trigger tumour necrosis factor (TNF)-dependent necroptosis, a type of caspase-independent cell death. In contrast to apoptosis, cells undergoing caspase-independent cell death generated a pro-inflammatory and immunogenic anti-tumour response through the activation of nuclear factor-κB (NF-κB). Specifically, this anti-tumour immune response, stimulated by caspase-independent cell death, involved tumour infiltration of T cells and activation of macrophages. Furthermore, and most importantly, engagement of caspase-independent cell death often led to complete tumour regression in the presence of an intact immune system in syngeneic colorectal cancer mouse models. Overall, this study highlights the potential value of inducing caspase-independent cell death as a more efficient means of treating cancer.