Leveraging ZBP1 signaling for cancer immunotherapy

Immune checkpoint inhibitors (ICIs) have transformed cancer care, yet durable responses remain limited in a majority of patients. This is particularly true of immunologically cold tumors, which are characterized by insufficient T-cell infiltration, low antigenicity, impaired adjuvanticity, and an immunosuppressive tumor microenvironment (TME). Z-form Nucleic Acid (Z-NA) Binding protein 1 (ZBP1)-initiated signaling, by overcoming these barriers, offers a mechanistic solution to rekindling ICI responsiveness in cold tumors. ZBP1 is an immune sensor which detects viral or endogenous Z-NAs, binds the kinase RIPK3, and activates Mixed Lineage Kinase Like pseudokinase (MLKL)-mediated necroptosis. ZBP1-initiated signaling can also inflame tumors non-cytolytically, including by activating inflammatory gene expression. Tumors frequently inactivate ZBP1 signaling, most notably by epigenetically silencing RIPK3. However, TME cells, particularly inflammatory cancer-associated fibroblasts (iCAFs), retain RIPK3 competence and represent a readily exploitable therapeutic vulnerability for activation of ZBP1-mediated immunogenic signaling within the tumor mass. Here, we discuss emerging strategies to activate ZBP1 within cold tumors as a means to enhance ICI-driven anti-tumor responses.