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Background Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterised by progressive multiorgan dysfunction. Direct investigation of human pancreatic tissue in SAP has been extremely limited, and effective targeted therapies are currently lacking.Objective We sought to define the cellular and molecular mechanisms of SAP progression to identify actionable therapeutic targets.Design Using rare pancreatic tissues from critically ill patients with SAP (n = 8), we constructed the first single-cell transcriptomic atlas of human SAP. Cellular compositional changes and intercellular communication were analysed to elucidate disease mechanisms. Findings were integrated with clinical data from a large patient cohort (n = 153) and validated through in vitro and in vivo studies in murine and porcine models.Results We identified pancreatic microcirculatory failure as a central pathological event in SAP, driven by CD8 + T cell-mediated endothelial injury. Mechanistically, tumour necrosis factor-alpha (TNF-α) upregulates UL16-binding proteins (ULBPs) on endothelial cells, activating the cytotoxic receptor NKG2D on infiltrating CD8+ T cells and creating a feed-forward loop that amplifies microvascular damage. The TNF-α/ULBP/NKG2D axis correlated with clinical disease severity and microcirculatory dysfunction in patients. In preclinical models, inhibition of TNF-α or CD8+ T cells preserved microvascular integrity, reduced tissue damage and improved survival.Conclusion This study provides the comprehensive cellular map of human SAP and uncovers a pathogenic immune-endothelial circuit—orchestrated by the TNF-α/ULBP/NKG2D axis—that drives microcirculatory dysfunction. These findings establish a mechanistic rationale for targeting TNF-α as a potential therapeutic strategy in SAP.