Abnormal glucose/lactate metabolism is one of the key hallmarks of a tumor. Leveraging the excessive metabolite lactate to generate reactive oxygen species (ROS) by lactate oxidase (LOx) has become an efficient method for cancer therapy. However, the hypoxic tumor microenvironment (TME) and ROS-scavenging enzymes largely restrict the catalytic activity of LOx. Herein, we design an ROS generator composed of LOx-encapsulated and 7-ethyl-10-hydroxycamptothecin (SN-38)- and tamoxifen (TAM)-coloaded membrane fusion liposomes, which can directly release cargoes via fusion with cancer cell membranes. Through the glycolysis promotion and mitochondrial respiration inhibition by TAM, and the antioxidant enzyme downregulation by SN-38, the generator not only spares oxygen and increases intracellular lactate for LOx catalysis to yield cytotoxic H 2 O 2 , but also avoids ROS removal, realizing triple-amplified ROS production and effective cancer cell killing. In the TME of an orthotopic breast cancer model, the generator consumes lactate and produces immunostimulatory H 2 O 2 , thereby promoting the M1-like polarization of tumor-associated macrophages and suppressing regulatory T cells to remodel the immunosuppressive TME. Additionally, the generator inhibits angiogenesis and further cancer metastasis via hypoxia inducible factor-1α (HIF-1α) signaling blockage. Collectively, this work provides an inspirational example of using a glucose/lactate metabolism interference strategy to fight against orthotopic triple-negative breast cancer.
The susceptibility of colorectal cancer (CRC) cells to Fusobacterium nucleatum (F. nucleatum) infection pose significant challenges to CRC treatment and prevention. This study addresses these challenges by mobilizing cGAS/STING axis activation and F. nucleatum-specific targeting, thereby achieving a multimodal treatment strategy for reversing the immunosuppressive microenvironment (ITM) and achieving targeted anti-F. nucleatum therapy. Specifically, a hybrid nanoplatform CuPpIX@HM was engineered using Escherichia coli and tumor cell membranes encapsulating ultrasound (US) stimulation-responsive copper protoporphyrin IX (CuPpIX). This design enables the precise accumulation of the nanoplatform at tumor sites following oral administration. Notably, upon US activation, CuPpIX generates a high level of reactive oxygen species (ROS), selectively eradicating F. nucleatum and exerting potent antitumor effects. Meanwhile, bacterial membrane components activate the cGAS/STING signaling pathway, effectively reversing the ITM, enhancing systemic antitumor immunity. Importantly, CuPpIX@HM exerts minimal disruption to healthy intestinal microbiota and remarkably increases the level of probiotics. In both orthotopic and liver metastasis, CRC models demonstrated that this strategy could significantly inhibit tumor growth and metastasis. Collectively, our study presents a highly targeted multimodal nanotherapy that holds strong potential to improve CRC treatment outcomes through the precision modulation of F. nucleatum and immune activation.
危险品化学品经营许可证（带存储）