通过抑制肿瘤糖酵解和避免适应性免疫抵抗的自递送纳米 PROTAC 的化疗结直肠癌免疫治疗,Advanced Science

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通过抑制肿瘤糖酵解和避免适应性免疫抵抗的自递送纳米 PROTAC 的化疗结直肠癌免疫治疗
Advanced Science ( IF 14.3 ) Pub Date : 2024-01-18 , DOI: 10.1002/advs.202309204
Lin‐Ping Zhao ₁ , Rong‐Rong Zheng ₂ , Xiao‐Na Rao ₂ , Chu‐Yu Huang ₂ , Hang‐Yu Zhou ₁ , Xi‐Yong Yu ₂ , Xue‐Yan Jiang ₂ , Shi‐Ying Li _{2,

3}

Affiliation

化疗药物的化疗调节能力对于解决结直肠癌的低免疫原性、免疫抑制性乳酸微环境和适应性免疫抵抗具有吸引力。在这项工作中，发现BRD4（dBET57）的蛋白水解靶向嵌合体（PROTAC）通过c-Myc的转录抑制下调结直肠癌糖酵解，同时抑制程序性死亡配体1（PD-L1）的表达以逆转免疫逃避并避免适应性免疫抵抗。_{在此基础上，通过多柔比星（DOX）和dBET57在DSPE-PEG 2000}的帮助下自组装，进一步制备了自递送纳米PROTAC（称为DdLD NPs）。DdLD NPs 可以提高 DOX 和 dBET57 的稳定性、细胞内递送和肿瘤靶向积累。同时，DdLD NPs的化疗作用可以有效破坏结直肠癌细胞，引发强烈的免疫原性细胞死亡（ICD）。更重要的是，DdLD NPs的化学调节作用可以抑制结直肠癌糖酵解，减少乳酸产生，并通过BRD4降解下调PD-L1表达。利用化疗和化疗调节能力，DdLD NPs 系统性地激活抗肿瘤免疫，抑制原发性和转移性结直肠癌的进展，而不引起任何全身副作用。这种自递送纳米 PROTAC 可能为化疗肿瘤免疫治疗提供新的见解。

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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.

更新日期：2024-01-19

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