Mechanism and role of regulated cell death in tumor immunity and immunotherapy

Abstract

Cancer immune checkpoint inhibitors (ICIs) have brought breakthroughs, but only about one-third of cancer patients benefit from ICIs. In recent years, targeting non-apoptotic regulated cell death (RCD) subtypes, such as ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis, has emerged as a novel strategy in cancer therapy due to their ability to release damage-associated molecular patterns (DAMPs), enhance antigen presentation, and remodel the tumor immune microenvironment, thereby activating anti-tumor immune responses. A number of studies have shown that precise induction of these pathways by small molecules or nanoparticles can reverse the resistance to chemoradiotherapy and ICIs, promote the transformation of “cold tumors” to “hot tumors,” and ultimately establish durable immune memory. This article systematically reviewed the key mechanisms and immunomodulatory functions of five types of non-apoptotic RCD (ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis), discussed the related treatment strategies, and prospects for the future application in combination with existing immunotherapy.

Keywords

regulated cell death / tumor immune microenvironment / tumor immunity / tumor immunotherapy

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2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.