| Author |
Chu T, Liu Z, Liu H, Mu W, Zhi Y, Sheng N, Zhang J, Peng X, Lv S, Duan K, Lou F, Liu H, Wang C, Zhou J, Liu X, Yang H, Liu Y, Xu J, Fan Z, Wei F.
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| Abstract |
Pancreatic ductal adenocarcinoma (PDAC) presents a therapeutic hurdle owing to its immunotherapy resistance and limited treatment options. Pyroptosis, a lytic inflammatory cell death pathway, holds promise for reversing immunosuppression in "cold" tumors, yet tumor-specific induction strategies remain unclear. Here, we employ a contrastive learning graph neural network to identify arachidonic acid (AA), an endogenous ω-6 polyunsaturated fatty acid, as a pan-cancer pyroptosis inducer operating through irreversible mitochondrial permeability transition inducing Caspase 3/GSDME activation. Crucially, a repurposed mitophagy machinery for non-autophagic functional scaffolding of Caspase 3/GSDME on autophagosomal membranes enables rapid pyroptotic execution. Pharmacological accumulation of autophagosomes amplifies AA-induced pyroptosis in PDAC organoids and patient-derived xenografts. Furthermore, AA-triggered pyroptosis, remodels immunosuppressive tumor microenvironments, boosting cytotoxic T cell infiltration and synergizing with anti-PD-1 therapy in immunocompetent models. Thus, our findings position AA as a candidate dual-function agent for pyroptosis-immune synergy, while autophagosome manipulation emerges as a strategy to potentiating strategy.
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