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<p>Why some tumors respond to immunotherapy (“hot” tumors) while others remain resistant (“cold” tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK–AKAP1–DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS–STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy</p>

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Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Andrea Palamidessi,
  • Emanuela Frittoli,
  • Monica Corada,
  • Emanuele Martini,
  • Leonardo Barzaghi,
  • Chiara Milanese,
  • Galina V. Beznoussenko,
  • Alessandro Lazzarin,
  • Edoardo N. Bellini,
  • Alexander A. Mironov,
  • Zeno Lavagnino,
  • Serena Magni,
  • Sara Barozzi,
  • Dario Parazzoli,
  • Laura Tizzoni,
  • Valentina Dall’Olio,
  • Valeria Cancila,
  • Patrizia Romani,
  • Melody Di Bona,
  • Renata Zobalova,
  • Stepana Boukalova,
  • Mattia Rediti,
  • Pier G. Mastroberardino,
  • Jiri Neuzil,
  • Marco Foiani,
  • Sirio Dupont,
  • Claudio Tripodo,
  • Giorgio Scita

摘要

Why some tumors respond to immunotherapy (“hot” tumors) while others remain resistant (“cold” tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK–AKAP1–DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS–STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy