Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai, 200092, China.
Institute of acoustics, School of Physics Science and Engineering, Tongji University, Shanghai, 200092, China.
Adv Sci (Weinh). 2022 May;9(14):e2104182. doi: 10.1002/advs.202104182. Epub 2022 Mar 20.
The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine-A2AR negative feedback pathway is highlighted during photothermal-induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal-induced ICD process. It is possible to achieve a robust ICD-based immunotherapy via targeting the adenosine-A2AR metabolic pathway. In this regard, an A2AR inhibitor-loaded polydopamine nanocarrier masked by an acid-sensitive PEG shell is designed to enable tumor-specific delivery and photothermal-induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8 T lymphocyte infiltration, and reducing the myeloid-derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials.
代谢物腺苷通过与其代谢检查点腺苷 2A 受体（A2AR）结合，在肿瘤微环境（TME）中发挥重要的免疫抑制作用。在这里，强调了光热诱导免疫原性细胞死亡（ICD）过程中的腺苷-A2AR 负反馈途径。在光热诱导的 ICD 过程中，ATP 水解产生的腺苷被放大。通过靶向腺苷-A2AR 代谢途径，可以实现强大的基于 ICD 的免疫疗法。在这方面，设计了一种负载 A2AR 抑制剂的聚多巴胺纳米载体，其被酸敏感的 PEG 壳屏蔽，以实现肿瘤特异性递送和光热诱导的 ICD 同时进行。到达酸性 TME 时，PEG 壳选择性地分离并暴露出粘附的聚多巴胺层，导致抑制剂在肿瘤组织中积累。积累的抑制剂减弱了腺苷的代谢抑制作用，并增强了 ICD 免疫反应。其通过促进树突状细胞（DC）的激活、增加 CD8 T 淋巴细胞的浸润以及减少髓样来源的抑制细胞（MDSC）群体来实现。此外，这种协同治疗显著消退了原发肿瘤，抑制了远端肿瘤的生长，并防止了肺转移。该研究强调了一种通过使用先进的纳米材料阻断代谢检查点 A2AR 来增强 ICD 免疫疗法效果的策略。
