An immunostimulant nanomedicine enhances radioimmunotherapy by remodeling the tumor immunosuppressive landscape after radiotherapy

This is the authors' abstract. We don't add key points for this paper.

Studies have shown that radiotherapy (RT) has powerful immune-stimulating effects. However, RT-mediated distal tumor regression is rare in clinical practice. Here, with an animal experimental model, we found that RT shaped an immunosuppressive landscape characterized by a high-influx of myeloid-derived suppressor cells (MDSCs), and the induction of immunologically silent tumor apoptosis, hindering the efficacy of radioimmunotherapy. To address this issue, we developed a spatiotemporally controlled nanomedicine for remodeling the immunosuppressive tumor microenvironment (TME) post-RT. Decitabine (DAC)-loaded ferritin (Ft) were crosslinked via an azobenzene linker, and meanwhile encapsulated with all-trans-retinoic acid (ATRA) to construct a Ft@DAC@ATRA nanoassembly (denoted as FD@ATRA), which dissociated into monodispersive Ft@DAC units in hypoxia TME. The released ATRA could eliminate immunosuppressive MDSCs, and meanwhile Ft@DAC selectively induced immunogenic pyroptosis of the tumor by targeting the transferrin receptor 1 overexpressed on the tumor to effectively activate CD8 + T cells. FD@ATRA treatment reshaped the tumor immune landscape post-RT with an increase of 16.8% in tumor-infiltrating IFN- γ + CD8 + T cells. Moreover, FD@ATRA-enhanced RT remained effective in large, treatment-resistant tumors, and the inhibition rate of FD@ATRA-enhanced RT on distant tumors improved by 47% compared to the RT group alone, providing an effective therapeutic approach to improve the clinical outcomes of radioimmunotherapy. The immunomodulatory FD@ATRA reshapes the tumor immune landscape after radiotherapy by eliminating myeloid-derived suppressor cells (MDSCs) and switching tumor apoptosis to immunogenic pyroptosis, thus enhancing radioimmunotherapy.