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 Tumor mechanics can shape immune responses, but precisely how remains unclear. Here, authors show that RAB5A-driven tissue fluidization damages mitochondria, releasing mitochondrial DNA that activates cGAS–STING immunity and sensitizes breast tumors to checkpoint blockade.
Palamidessi et al. (Wed,) studied this question.