Hyperbaric oxygen regulates tumor mechanics and augments Abraxane and gemcitabine antitumor effects against pancreatic ductal adenocarcinoma by inhibiting cancer-associated fibroblasts

While the combination of Abraxane and gemcitabine (GEM) has been approved as a first-line therapy for the treatment of advanced pancreatic ductal carcinoma (PDAC), the clinical antitumor efficacy is dismal thus far. Here, we explore hyperbaric oxygen (HBO) therapy to boost antitumor efficacy of Abraxane and GEM against murine PDAC Panc02 tumors. Mechanistically, we reveal that HBO significantly constrains cancer-associated fibroblasts (CAFs) by disrupting hypoxia. As CAFs are the main producers of extracellular matrix (ECM) components, HBO effectively reduces collagen Ⅰ and fibronectin, leading to normalization of not only tumor mechanics but also blood vessels. Therefore, HBO augments drug delivery in terms of tumor accumulation, penetration, and cellular internalization. Furthermore, we demonstrate that HBO helps Abraxane and GEM eliminate cancer stem cells (CSCs) by regulating CAFs mediated CSCs niche. Consequently, HBO potentiates antitumor efficacy of Abraxane and GEM by inhibiting not only primary tumors but more importantly metastases of Panc02 tumors, with negligible side effects. Given HBO, Abraxane, and GEM are routinely applied in clinical practice, their combination is readily translatable to bedside applications.