Nanoreactors with Cascade Catalytic Activity Reprogram the Tumor Microenvironment for Enhanced Immunotherapy by Synchronously Regulating Treg and Macrophage Cells.

ABSTRACT

Immunotherapy has been extensively utilized and studied as a prominent therapeutic strategy for tumors. However, the presence of a hypoxic immunosuppressive tumor microenvironment significantly reduces the efficacy of the treatment, thus impeding its application. In addition, the hypoxic microenvironment can also lead to the enrichment of immunosuppressive cells and reduce the effectiveness of tumor immunotherapy; nanoparticles with biocatalytic activity have the ability to relieve hypoxia in tumor tissues and deliver drugs to target cells and have been widely concerned and applied in the field of tumor therapy. The present study involved the development of a dual nanodelivery system that effectively targets the immune system to modify the tumor microenvironment (TME). The nanodelivery system was developed by incorporating R848 and Imatinib (IMT) into Pt nanozyme loaded hollow polydopamine (P@HP) nanocarriers. Subsequently, their surface was modified with specifically targeted peptides that bind to M2-like macrophages and regulatory T (Treg) cells, thereby facilitating the precise targeting of these cells. When introduced into the tumor model, the nanocarriers were able to selectively target immune cells in tumor tissue, causing M2-type macrophages to change into the M1 phenotype and reducing Treg activation within the tumor microenvironment. In addition, the carriers demonstrated exceptional biocatalytic activity, effectively converting H2O2 into oxygen and water at the tumor site while the drug was active, thereby alleviating the hypoxic inhibitory conditions present in the tumor microenvironment. Additionally, this further enhanced the infiltration of M1-type macrophages and cytotoxic T lymphocytes. Moreover, when used in conjunction with immune checkpoint therapy, the proposed approach demonstrated enhanced antitumor immunotherapeutic effects. The bimodal targeted immunotherapeutic strategy developed in the present study overcomes the drawbacks of traditional immunotherapy approaches while offering novel avenues for the treatment of cancer.