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. Radiotherapy–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.