目前可用的免疫检查点疗法对多形性胶质母细胞瘤（GBM）的治疗效果令人失望，发现更好的免疫检查点并开发创新的靶向策略具有重要意义。肿瘤中发现的代谢免疫检查点胞外-5-核苷酸酶（CD73）由于细胞外腺苷（ADO）失调而导致肿瘤的免疫逃避，显着抑制抗肿瘤T细胞的功能并增加免疫抑制细胞的活性。在此，我们通过使用多功能 Au@Cu2-xSe 纳米颗粒（ACS NP）来显着抑制 CD73 的表达，从而减少 ADO 的产生。 ACS NPs 可以通过 Fenton 样反应减轻肿瘤缺氧，从而降低 CD73 的表达，从而减弱 ADO 驱动的免疫抑制，从而增强抗肿瘤 T 细胞浸润和 GBM 活性。 ACS NPs释放的铜离子(Cu2+)可以与二硫化物螯合，形成细胞毒性的双(N,N-二乙基二硫代氨基甲酸酯)-铜络合物(CuET)，该络合物可以与放射治疗相结合，招募更多的抗肿瘤T细胞浸润进入肿瘤部位。基于抑制CD73促进抗肿瘤T细胞的浸润和活性，可以实现级联增强GBM免疫治疗效果。肿瘤内CD8 T和CD4 T细胞以及脾脏中记忆T细胞的显着增加，有效地将肿瘤尺寸缩小了92%，这证明了代谢免疫检查点CD73抑制与放化疗相结合的免疫治疗的优异疗效。这项工作表明，调节 CD73 介导的肿瘤免疫抑制是改善 GBM 免疫治疗结果的重要策略。

The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2-xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.