Hollow manganese dioxide/copper-doped carbon dot nanoplatform reshapes the tumor microenvironment to enhance the immune therapy response.

Immune checkpoint blockade (ICB) therapy has great potential in cancer therapy, but the patient response rate is low, mainly limited by hypoxia and insufficient infiltration of immunocompetent T cells in the immunosuppressive tumor microenvironment (TME), and Hypoxia-inducible factor-1α (HIF-1α) mediated high Programmed Cell Death-Ligand 1 (PD-L1) expression. In this study, hyaluronic acid (HA) modified hollow manganese dioxide (HMnO₂) nanocarriers (MCCMPH) were constructed via an innovative "in-situ synthesis-template etching" strategy to solve the above problems: this strategy physically locks copper-doped carbon dots (CuCDs) in the HMnO₂ cavity, addressing the issue of carbon dot detachment in traditional MnO2@CDs materials. The nanocarrier is loaded with PDT photosensitizer methyl pyropheophorbide a (MPPa) and CuCDs with chemodynamic therapy (CDT)/photothermal therapy (PTT) functions. MCCMPH targets CD44 receptors on the surface of tumor cells through HA for precise delivery; HMnO2 decomposes to produce oxygen in the tumor microenvironment, improves hypoxia, downregulates HIF-1α and PD-L1, and provides oxygen substrates for photodynamic therapy (PDT). The CDT and PTT of CuCDs synergistically interact with the PDT of MPPa, depleting glutathione (GSH) to cascade amplification of reactive oxygen species (ROS), significantly enhancing immunogenic death (ICD). In vitro and in vivo experiments have shown that MCCMPH can promote dendritic cell maturation, tumor-associated macrophage polarization from M2 to M1, and increase CD4+/CD8+T cell infiltration. In the dual-tumor model, it was combined with ICB to significantly inhibit the growth of primary and distant tumors, which proved to be effective in reversing the immunosuppressive TME and providing a new strategy for improving ICB response rate.