Lighting a Fire: Can We Harness Pyroptosis to Ignite Antitumor Immunity?

Abstract The impressive success of current cancer immunotherapy in some patients but lack of effectiveness in most patients suggests that additional strategies to promote antitumor immunity are needed. How cancer cells die, whether spontaneously or in response to therapeutic intervention, has a profound effect on the type of immune response mobilized. Here, we review research that highlights a previously unappreciated role of gasdermin-mediated inflammatory death (pyroptosis) to promote antitumor immunity and identifies gasdermin E as a tumor suppressor. Immune elimination of tumor cells by natural killer cells and cytotoxic T lymphocytes, which is the final key event in antitumor immunity, was previously thought to be noninflammatory. The research shows that gasdermin expression in tumor cells converts immune cell–mediated killing to inflammatory pyroptosis when cell death–inducing granzymes directly cleave and activate gasdermins. Granzyme B cleaves gasdermin E, and granzyme A cleaves gasdermin B. The data suggest the potential to harness pyroptosis in the tumor to ignite an effective immune response to immunologically cold tumors. Gasdermin expression also augments toxicity of cancer therapy—gasdermin E expression by B-cell leukemias and lymphomas is a root cause of chimeric antigen receptor (CAR) T–cell cytokine storm, and its expression in normal tissues promotes the toxicity of chemotherapeutic drugs. Even though our knowledge about the role of pyroptosis in cancer is growing, there is still a lot to learn—what activates it, how it is regulated, when it is beneficial, and how it can be harnessed therapeutically to improve cancer immunotherapy or reduce therapy-related toxicity.