Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer

Abstract

Abstract Tumor-associated bacteria (TAB) play a critically important role in regulating the microenvironment of a tumor, which consequently greatly deteriorates the therapeutic effects by chemo- and radiotherapy deactivation and, more considerably, leads to substantial immunosuppression. On the contrary, herein we propose a nanocatalytic tumor-immunotherapeutic modality based on the bacteria disintegration by bacteria-specific oxidative damage under magnetic hyperthermia for highly effective immune response activation-promoted tumor regression. A monodispersed and superparamagnetic nanocatalytic medicine modified by arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP), named as MNP-RGD-TPP herein, has been synthesized, which features selective accumulation at the TAB by the electrostatic affinity, enabling effective TAB disintegration by the nanocatalytic Fenton reaction producing abundant cytotoxic hydroxyl radicals in situ under alternating magnetic field-induced hyperthermia. More importantly, the lipopolysaccharide has been metabolically secreted from the destructed TAB as pathogen-associated molecular patterns (PAMPs) to M1-polarize tumor-associated macrophages (TAMs) and promote the maturation of dendritic cells (DCs) for innate immuno-response activation of TAMs, followed by cytotoxic T lymphocytes awakening under the PAMPs presentation by the mature DCs against tumor cells. The integrated innate and adaptive immunity activations based on this TAB-promoted nanocatalytic immunomedicine, instead of magnetic heating-induced hyperthermia or the released Fe2+/Fe3+ Fenton agent, has been found to achieve excellent therapeutic efficacy in an orthotopic colorectal cancer model, demonstrating the great potential of such an integrated immunity strategy in clinical tumor immunotherapy.