An immunogenic cell death dual-nanoamplifier for the reverse of chemotherapy resistance and immune escape in metastatic colon cancer

Abstract

Liver metastasis is the most common type of colon cancer distant metastasis, characterized by a high incidence and mortality. Irinotecan, an immunogenic cell death inducer, has become the first-line drug for advanced colon cancer liver metastasis. Inevitably, the majority of patients treated with irinotecan experience drug resistance and develop immune escape over time. To amplify the therapeutic effect of irinotecan, a novel dual-amplification strategy was proposed here, using irinotecan, BRD4 PROTAC (MZ1), and PD-L1 siRNA co-delivery system. In this system, MZ1, serving as the primary amplifier module, could harness the cell’s natural degradation process to reduce the protein level of BRD4, thereby managing irinotecan resistance. Meanwhile, PD-L1 siRNA, functioning as the secondary amplifier module, could down-regulate the expression of cell surface protein PD-L1, thus reversing the immune escape. The “minimalist” self-assembly system employed intermolecular non-covalent interactions between drugs and realized simultaneous regulation of intracellular and extracellular proteins in tumor cells. This dual-nanoamplifier effectively inhibited tumor proliferation, promoted apoptosis, and suppressed the growth of colon cancer liver metastasis, providing a potential solution to address the clinical challenges posed by chemotherapy resistance and immune escape associated with irinotecan in the treatment of colon cancer liver metastasis.