Tumor stroma plays an important role in the occurrence, development, and metastasis of colorectal cancer (CRC). The dense collagenous stroma forms a physical barrier for antitumor drugs and sustains a highly tumor immunosuppressive microenvironment. To address this issue, a spatiotemporal combination of antitumor stroma and nanoscale functional materials was used as an antitumor strategy for reprogramming the tumor immune microenvironment. In this combination, metformin hydrochloride (MET) was intraperitoneally injected to disrupt the dense tumor stroma for promoting drug delivery and remodeling the tumor immune microenvironment. Subsequently, intravenously injected multifunctional drug-delivery materials (MIL-100/mitoxantrone/hyaluronic acid nanoparticles, MMH NPs) were visualized by double imaging (photoacoustic (PA) and fluorescence imaging) and generated a robust immune response via immunogenic cell death (ICD). More importantly, the combination treatment also acted synergistically with the anti-OX40 agonist antibody (αOX40), which enhanced the treatment of orthotopic CRC. In summary, the combination strategy of MET/MMH NPs/αOX40 provides a novel and effective clinical option for CRC therapy.

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