Gu Jingjing, Chang Jiao, Chen Shiyu, Zhi Hui, Sun Jiuyuan, Yin Weimin, Zhang Tingting, Zang Jie, Zhao Yuge, Liu Yiqiong, Zheng Xiao, Feng Leiyu, Li Yongyong, Dong Haiqing
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration Ministry of Education Tongji Hospital The Institute for Biomedical Engineering & Nano Science School of Medicine Tongji University Shanghai 200092 P. R. China.
Shanghai Skin Disease Hospital The Institute for Biomedical Engineering & Nano Science School of Medicine Tongji University Shanghai 200092 P. R. China.
Small Sci. 2024 Feb 5;4(4):2300242. doi: 10.1002/smsc.202300242. eCollection 2024 Apr.
Cell metabolite adenosine can induce extensive and persistent immunosuppression by binding to adenosine receptors on immune cells. Seriously, the hypoxia-driven adenosinergic axis aggravates adenosine accumulation via dephosphorizing immune-activating adenosine triphosphate (ATP) released during immunogenic cell death (ICD). Different from direct adenosine clearance or adenosine receptor blockade or directly using ecto-enzyme (CD39/CD73) antagonist, it is hoped to use an innovative small science engineering to regulate the upstream hypoxia/HIF-1α signal of the hypoxia-adenosinergic axis, thereby reducing the immunosuppressive extracellular adenosine and enhancing ICD-triggered antitumor immunity. PM@Mn is constructed by gradually integrating metformin and MnO on polydopamine (PDA) nanoparticles. PM@Mn can effectively suppress hypoxia-adenosinergic axis via combining catalytic oxygen production with reduced endogenous oxygen consumption. Such motif of hypoxia relief suppresses the metabolism of ATP to adenosine via down-regulating the expression of HIF-1α, CD39, and CD73. Meanwhile, PDA in PM@Mn can induce local tumor ablation and trigger the "vaccine effect" of ICD under near-infrared radiation. In a mouse breast cancer model with low immunogenicity, our strategy can effectively reduce adenosine accumulation, PM@Mn group exhibits 4.51-fold cytotoxic T lymphocyte infiltration and tumor inhibition rate of 75.4%. This study provides a new strategy to advance ICD-triggered antitumor immunity through supressing hypoxia-adenosinergic axis.
细胞代谢产物腺苷可通过与免疫细胞上的腺苷受体结合，诱导广泛且持久的免疫抑制。严重的是，缺氧驱动的腺苷能轴通过使免疫原性细胞死亡（ICD）期间释放的免疫激活型三磷酸腺苷（ATP）去磷酸化，加剧腺苷积累。与直接清除腺苷、阻断腺苷受体或直接使用胞外酶（CD39/CD73）拮抗剂不同，人们希望利用一种创新的小型科学工程来调节缺氧-腺苷能轴的上游缺氧/HIF-1α信号，从而减少免疫抑制性细胞外腺苷，并增强ICD触发的抗肿瘤免疫力。PM@Mn是通过将二甲双胍和MnO逐步整合到聚多巴胺（PDA）纳米颗粒上构建而成。PM@Mn可通过将催化产氧与降低内源性氧消耗相结合，有效抑制缺氧-腺苷能轴。这种缓解缺氧的模式通过下调HIF-1α、CD39和CD73的表达，抑制ATP向腺苷的代谢。同时，PM@Mn中的PDA可在近红外辐射下诱导局部肿瘤消融并触发ICD的“疫苗效应”。在低免疫原性的小鼠乳腺癌模型中，我们的策略可有效减少腺苷积累，PM@Mn组的细胞毒性T淋巴细胞浸润增加4.51倍，肿瘤抑制率达75.4%。本研究提供了一种通过抑制缺氧-腺苷能轴来增强ICD触发的抗肿瘤免疫力的新策略。
