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<p>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.</p>

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Arachidonic acid induces pyroptosis via a non-autophagic function of mitophagy and enhances immunotherapy in a PDAC model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Tongjia Chu,
  • Ziyu Liu,
  • Huan Liu,
  • Wentao Mu,
  • Yao Zhi,
  • Nan Sheng,
  • Jian Zhang,
  • Xinyu Peng,
  • Shengnan Lv,
  • Kehang Duan,
  • Fengxiang Lou,
  • Han Liu,
  • Chuanlei Wang,
  • Jianpeng Zhou,
  • Xingyu Liu,
  • Haocheng Yang,
  • Yunzhi Liu,
  • Jingtong Xu,
  • Zhongqi Fan,
  • Feng Wei

摘要

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.