Hyperbaric oxygen augments Doxil antitumor efficacy by reducing tumor-induced lactate

Compared to healthy individuals, cancer patients exhibit significantly elevated lactate. While numerous studies have revealed the critical role of lactate in fostering an immunosuppressive tumor microenvironment, the effects of lactate on cancer nanomedicine (e.g., Doxil) or drug delivery remain largely elusive. This study demonstrates that elevated lactate by tumor accelerates hepatic clearance of Doxil through increasing the proportion of M2-polarized Kupffer cells, while hyperbaric oxygen (HBO) reverses this process. HBO inhibits glycolysis by increasing oxygen availability, thereby reducing lactate production in both tumor and normal tissues. The resulting lactate reduction diminishes M2 polarization of Kupffer cells, reduces Doxil uptake in the liver, and prolongs its blood circulation time, ultimately enhancing anti-tumor efficacy. These findings not only elucidate the critical role of lactate in drug delivery, but also establish HBO as an effective strategy to constrain tumor-derived lactate. This research offers valuable insights with significant implications for cancer nanomedicines.