Unleashing necroptosis: Transforming the tumor immune microenvironment for cancer therapy

Necroptosis, a regulated form of inflammatory cell death, is increasingly recognized as a pivotal modulator of the tumor immune microenvironment (TME). In contrast to the typically non-immunogenic nature of apoptosis, necroptosis is highly immunogenic, primarily involving the release of damage-associated molecular patterns (DAMPs) that activate both innate and adaptive immunity. This review comprehensively examines the role of necroptosis in cancer immunity. We first discuss how the expression of necroptosis-related genes correlates with immune cell infiltration and patient prognosis across various cancers. The review further details the mechanisms by which necroptosis influences the function of key immune cells, including dendritic cells, tumor-associated macrophages, and T cells. Moreover, we explore how necroptotic cancer cells shape antitumor immune responses by regulating the infiltration and activity of immune cells within the TME. For therapeutic strategies, we highlight emerging platforms such as inducible gene systems, mRNA delivery, and nanotechnology, which are designed to specifically induce tumor necroptosis and show significant potential in reversing the immunosuppressive TME. A deeper understanding of this context-dependent cell death pathway is crucial to advance cancer immunotherapy.