Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy

Abstract

Unleashing the immune system with immune checkpoint inhibitors (ICI) has significantly improved overall survival for subsets of patients with stage III/IV cancer. However, many tumors are nonresponsive to ICIs, in part due to a lack of tumor-infiltrating lymphocytes (TIL). Converting these immune “cold” tumors to “hot” tumors that are thus more likely to respond to ICIs is a major obstacle for cancer treatment. Triggering inflammatory forms of cell death, such as necroptosis and pyroptosis, may alter the tumor immune microenvironment and the influx of TILs. We present an emerging view that promoting tumor-localized necroptosis and pyroptosis may ultimately enhance responses to ICI. Significance: Many tumor types respond poorly to ICIs or respond but subsequently acquire resistance. Effective therapies for ICI-nonresponsive tumors are lacking and should be guided by evidence from preclinical studies. Promoting inflammatory cell death mechanisms within the tumor may alter the local immune microenvironment toward an ICI-responsive state.