Multifunctional Nanoregulator Reshapes Immune Microenvironment and Enhances Immune Memory for Tumor Immunotherapy

Hypoxia leads to up-regulation of PD-L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO₂ particles and small molecular IPI549 is developed, which can reshape the tumor immune microenvironment (TIME) to unleash the immune system. The intravenously administered nanoregulator effectively accumulates in tumor sites to alleviate hypoxia via oxygen-generating reduction of MnO₂ and to inhibit PI3Kγ on MDSCs via IPI549 release in the tumor microenvironment (TME), which results in concurrent downregulation of PD-L1 expression, polarization of tumor associated macrophages (TAMs) toward pro-inflammatory M1-like phenotype (tumor-suppressive), enhanced infiltration of CD4⁺ helper T lymphocytes (Th cells), and cytotoxic CD8⁺ T lymphocytes (Tc cells), and suppressed infiltration of regulatory T lymphocytes (T_reg cells) for effective tumor immunotherapy. Furthermore, the local generation of Mn²⁺ in TME allows tumor-specific magnetic resonance imaging (MRI). More excitingly, the nanoregulator-reshaped TIME is effectively reserved due to the synergistic effect of hypoxia alleviation and MDSC PI3Kγ inhibition, leading to remarkable post-medication inhibition of tumor re-growth and metastasis in an animal study.