Reprogramming of Neutrophils as Non-canonical Antigen Presenting Cells by Radiotherapy-Radiodynamic Therapy to Facilitate Immune-Mediated Tumor Regression

Ineffective antigen cross-presentation in the tumor microenvironment compromises the generation of antitumor immune responses. Radio-therapy-radiodynamic therapy (RT-RDT) with nanoscale metal-organic frameworks (nMOFs) induces robust adaptive immune responses despite modest activation of canonical antigen presenting dendritic cells. Here, using transplantable and autochthonous murine tumor models, we demonstrate that RT-RDT induces antitumor immune responses via early neutrophil infiltration and reprogramming. Intravenous or intratumoral injection of nMOFs recruited peripheral CD11b(+)Ly6G(+)CD11c(-) neutrophils into tumors. The activation of nMOFs by low- dose X- rays significantly increased the population of CD11b(+)Ly6G(+)CD11c(+) hybrid neutrophils with upregulated expression of the co-stimulatory molecules CD80 and CD86 as well as major histocompatibility complex class II molecules. Thus, nMOF-enabled RT-RDT reshapes a favorable tumor microenvironment for antitumor immune responses by reprogramming tumor-infiltrating neutrophils to function as non-canonical antigen presenting cells for effective cross-presentation of tumor antigens.