Immune-regulating bimetallic metal-organic framework nanoparticles designed for cancer immunotherapy.

Immunogenic cell death (ICD) is a promising strategy in cancer immunotherapy to induce high immunogenicity and activate the immune system. However, its efficacy is counteracted by the concurrent exposure of phosphatidylserine (PS), an immunosuppressive signal on the surface of cancer cells. Here we report the synthesis of a bimetallic metal-organic framework (MOF) nanoparticle containing Gd3+ and Zn2+ (Gd-MOF-5) that can be used as an immunomodulator to downregulate the immunosuppressive PS signal and an ICD inducer to upregulate immunostimulatory signals. Gd3+ inhibits PS externalization via inhibiting the activity of scramblase, an enzyme to transfer PS to the outer leaflet of plasma membrane. Moreover, intracellular Zn2+ overload activates endoplasmic reticulum stress for ICD induction. In combination with an immune checkpoint inhibitor (PD-L1 antibody, denoted as aPDL1), Gd-MOF-5 activated potent immune response and effectively inhibited primary and distal tumor growth in a bilateral 4T1 tumor model. This work presents a new strategy using designed MOF materials to modulate the cell signalling and immunosuppressive microenvironment to improve the outcome of cancer immunotherapy.