Pan-cancer analysis of a novel indicator of necroptosis with its application in human cancer

As a type of programmed cell death, necroptosis is thought to play a dual role in tumorigenesis. However, a comprehensive assessment of necroptosis-related regulators across human cancers has not been reported. Therefore, in this study, we established a quantitative index to evaluate the necroptosis rate and determine its correlations with clinical prognosis, signaling pathways and molecular features, immune cell infiltration and regulation, immunotherapy, and chemotherapy sensitivity across cancers. Our results indicated that the necroptosis score can act as a favorable or risky prognostic factor in various cancer types. A gene set variation analysis suggested that necroptosis is significantly associated with immune- and inflammation-related signaling pathways, cell growth and apoptosis, and energy metabolism. Furthermore, necroptosis can affect the tumor microenvironment and immunity regulation, and the effect of necroptosis on immunity is different in different tumor types. There is crosstalk between components of necroptosis, pyroptosis, ferroptosis and autophagy pathways in multiple types of cancers. Finally, the necroptosis rate can be an indicator of immunotherapy effectiveness in multiple cancers and can affect the chemotherapy sensitivity of cancer cells. Our study presents a characterization of necroptosis across human cancers, highlights the potential necroptotic effects on immune regulation, and provides new insights into the development of individualized tumor treatments and clinical applications of immunotherapy.