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BackgroundNeutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed.MethodsWe systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups.ResultsA gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs.ConclusionNETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.