Multifunctional Ca2+ nanomodulators regulate type I interferon pathway to remodel tumor microenvironment for cancer immunotherapy

Although immune checkpoint blockade (ICB) therapy has been widely used for the treatment of a variety of cancers, its therapeutic efficacy is severely impaired by low tumor immunogenicity and the immunosuppressive microenvironment. Herein, we designed multifunctional immunomodulatory calcium nanoparticles to reshape the immunosuppressive tumor microenvironment. Our multifunctional calcium nanoparticles, CD@CaCO3P, are designed to release calcium ions and doxorubicin (DOX) into the acidic tumor microenvironment, which synergistically increase the tumor cell calcium ion concentration, while the release of combretastatin A4 phosphate (CA4P) further enhances T cell infiltration. Specifically, CD@CaCO3P effectively mediates the immunogenic cell death (ICD) of tumor cells and triggers the activation of nuclear factor kappa-B (NF-κB)/interferon regulatory factor 3 (IRF3), thereby regulating type I interferon (IFN-I) signaling pathways, and ultimately reprogramming the immunosuppressive tumor microenvironment by inducing M1-like macrophage polarization, promoting dendritic cell maturation, and increasing the infiltration of CD8+ T cells. Furthermore, CD@CaCO3P significantly increased tumor susceptibility to α-PD-1 checkpoint blocking immunotherapy and enhanced systemic immunotherapy performance against both primary and metastatic tumors. Our work provides new insights for the use functional calcium nanoparticles that modulate the tumor microenvironment to enhance the efficacy of cancer immunotherapy.