Reprogramming RIPK3-induced cell death in malignant B cells promotes immune-mediated tumor control

Cancer therapies that induce immunogenic cell death such as necroptosis can arm the immune system to clear residual tumor cells. Receptor-interacting serine/threonine protein kinase 3 (RIPK3) signaling can trigger necroptosis, orchestrating immune responses to solid tumors. Whether RIPK3 activity can be exploited for controlling B cell malignancies remains unclear. Here, we establish a strategy to manipulate RIPK3 activity in malignant B cells and promote immune-mediated tumor control. By controlling and visualizing RIPK3 signaling using intravital imaging, we established that RIPK3 activation promoted apoptosis and rapid macrophage engulfment but failed to induce necroptosis due to limited MLKL expression in B-lineage cells. RIPK3-induced cell death could be diverted toward necroptosis with type I IFN and caspase inhibition. Exploiting these findings, we showed that a combination therapy activating RIPK3 with SMAC mimetics while suppressing caspase activity and providing type I IFN resulted in immune-mediated control of B cell tumors. Hence, reprogramming RIPK3 activity represents an attractive therapeutic opportunity to target B cell malignancies.