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<p>The development of in situ tumor vaccines has been limited by the lack of delivery systems with precise tumor selectivity. Here, we show that mitochondria from cancer-associated fibroblasts (CAFs) exhibit an efficient tumor-homing property. We find that enrichment of the RHOT1/2 complex on the mitochondria mediates selective uptake by cancer cells through ITSN1-dependent clathrin endocytosis. Using this insight, we engineer RHOT1/2-enriched mitochondrial outer membranes into nanoscale vesicles (RMNPs) that preserve this intrinsic targeting capacity. In multiple mouse cancer models, RMNPs loaded with an immune-stimulating agent (TLR7/8 agonist) and gold nanoparticles enable photothermal therapy, which releases tumor antigens and activates antigen-presenting cells. This generates strong CD8⁺ T cell responses and long-lasting protection against tumor rechallenge. These findings reveal a fundamental organelle-based mechanism of selective intercellular targeting and establish a mechanism-driven platform with translational potential for cancer immunotherapy, highlighting how natural cellular and molecular biology can be harnessed for precision medicine.</p>

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RHOT1/2-driven mitochondrial membrane vesicles confer tumor-homing selectivity and enable in situ cancer vaccination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Wanrong Meng,
  • Bo Li,
  • Chang Cao,
  • Jialu He,
  • Bingzhi Li,
  • Yuhang Xie,
  • Jiajing Gong,
  • Wenxuan Wang,
  • Rong He,
  • Xuelei Ma,
  • Guiquan Zhu,
  • Longjiang Li

摘要

The development of in situ tumor vaccines has been limited by the lack of delivery systems with precise tumor selectivity. Here, we show that mitochondria from cancer-associated fibroblasts (CAFs) exhibit an efficient tumor-homing property. We find that enrichment of the RHOT1/2 complex on the mitochondria mediates selective uptake by cancer cells through ITSN1-dependent clathrin endocytosis. Using this insight, we engineer RHOT1/2-enriched mitochondrial outer membranes into nanoscale vesicles (RMNPs) that preserve this intrinsic targeting capacity. In multiple mouse cancer models, RMNPs loaded with an immune-stimulating agent (TLR7/8 agonist) and gold nanoparticles enable photothermal therapy, which releases tumor antigens and activates antigen-presenting cells. This generates strong CD8⁺ T cell responses and long-lasting protection against tumor rechallenge. These findings reveal a fundamental organelle-based mechanism of selective intercellular targeting and establish a mechanism-driven platform with translational potential for cancer immunotherapy, highlighting how natural cellular and molecular biology can be harnessed for precision medicine.