Chemotherapy-Enabled Colorectal Cancer Immunotherapy of Self-Delivery Nano-PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance

The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy. Self-delivery nano-PROTACs (designated as DdLD NPs) are fabricated by the self-assembly of doxorubicin and dBET57 with the assistance of DSPE-PEG2000. Chemo-regulation effect of DdLD NPs can inhibit glycolysis to improve immunosuppressive lactate microenvironment, and simultaneously downregulate PD-L1 expression to decrease adaptive immune resistance, thereby systemically activating the immunotherapy of metastatic colorectal cancer.image