Manganese nanosheets loaded with selenium and gemcitabine activate the tumor microenvironment to enhance anti-tumor immunity.

Breast cancer is among the most common malignant tumors globally. Despite advances in immunotherapy and targeted therapies, chemotherapy remains the primary clinical treatment. Gemcitabine, a cytosine nucleoside analog, is widely used for various solid tumors; however, its effectiveness is often limited by drug resistance and adverse side effects. In this study, we developed a novel drug delivery system, Mn/Se-Gem, designed to target tumor cells overexpressing CD44 and facilitate the controlled release of gemcitabine. This system exploits gemcitabine's pH sensitivity and HA-mediated CD44 targeting to induce DNA damage. Simultaneously, it neutralizes the acidic tumor microenvironment and releases nano-selenium and manganese ions, which promote the excessive production of reactive oxygen species (ROS), leading to mitochondrial damage and enhanced apoptosis of cancer cells. Furthermore, Mn (II) activates the cGAS-STING pathway, increasing susceptibility to ROS-induced DNA double-strand breaks, promoting macrophage maturation, inhibiting M2 polarization, and enhancing the cytotoxic function of T lymphocytes against tumor cells. In summary, this combination of chemotherapy and immunotherapy presents a promising strategy for the treatment of breast cancer.