Cascade-Synergistic Modulation of Intestinal Microbiota and Immune Microenvironment in Photothermal Orthotopic Colorectal Cancer Therapy

Colorectal cancer (CRC) has become one of the major threats to public health. Surgical operation combined with chemotherapy intervention is currently the main clinical approach for treating malignant CRC. The progression of this malignancy is frequently associated with the disruptions to the intestinal microbiota and an immunosuppressive landscape within the tumor microenvironment, both of which contribute to an increased propensity for tumor recurrence and metastatic spread. However, traditional treatment strategies, as well as emerging tumor immunotherapies, often result in severe gastrointestinal adverse events (AEs) and a dysregulated immune microenvironment, which fail to make significant progress in the efficacy of CRC treatment. It is essential to explore a holistic approach that incorporates modulation of the microbial and immune microenvironments for the treatment of CRC. In this study, we provide an alternative transabdominal photothermal therapy (PTT) for CRC that utilizes a novelty designed photothermal functional assembled drug (MnBV@DPHA NPs) administered orally. We employ PTT to precisely ablate orthotopic tumors, and achieved a cascade synergistic modulation of the intestinal microbiota and immune microenvironment, thereby enhanced the therapeutic efficacy of CRC. The oral assembled drug effectively targeted the tumor, precisely thermo-ablated cancer lesion while sparing healthy tissue. The aforementioned treatment strategy significantly reduced the presence of pathogenic bacteria and increased the proportion of probiotics within the intestinal microenvironment, thereby restoring the intestinal microbiota’s homeostasis. Furthermore, it reshaped the immunosuppressive microenvironment of CRC, thereby maintaining an immune homeostasis. Further research has confirmed that the cascade synergistic between the intestinal microbiota and the immune microenvironment enhances the efficacy of PTT and inhibits the recurrence and metastasis of CRC.