Yang Jiazhen, Su Tianqi, Wang Qinqi, Shi Run, Ding Jianxun, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026, P. R. China.
Adv Mater. 2025 Mar;37(12):e2419033. doi: 10.1002/adma.202419033. Epub 2025 Feb 14.
Inappropriate glucose metabolism in cancer cells is associated with immunosuppressive tumor microenvironments (TMEs). Although glycolysis inhibition enhances T cell-mediated immune responses, the integrated platforms combining glycolysis inhibition with immunotherapy remain underdeveloped. To address this gap, a glucose metabolism-targeted poly(amino acid) nanoformulation of oxaliplatin(IV)-aspirin prodrug (NP/OXA-ASP) is developed to improve chemo-immunotherapy by suppressing tumor glycolysis. This poly(amino acid) nanoparticle exhibits selective release, discharging 90.0% of OXA-ASP under reductive conditions within 36 h. Furthermore, over 80% of the prodrug converts to OXA and ASP within 12 h, promoting mitochondrial damage and glycolysis inhibition, which amplifies immunogenic cell death induced by OXA. In addition, suppressing glycolytic flux reduces lactate leakage, mitigating the immunosuppressive TMEs. Together, these mechanisms contribute to stronger chemo-immunotherapy efficacy. Compared to the OXA plus ASP formulation, NP/OXA-ASP demonstrates superior performances, reducing lactate levels at the tumor site by 25.4%, increasing the proportion of cytotoxic T lymphocytes by 1.53 times, decreasing the proportion of regulatory T cells by 2.20 times, and improving 1.39-fold of the tumor inhibition rate. These findings underscore that NP/OXA-ASP is a promising platform for integrating tumor metabolic regulation with immunomodulation and holds significant potential for advancing clinical chemo-immunotherapy.
癌细胞中不适当的葡萄糖代谢与免疫抑制性肿瘤微环境（TME）相关。尽管糖酵解抑制可增强T细胞介导的免疫反应，但将糖酵解抑制与免疫疗法相结合的整合平台仍未得到充分发展。为了弥补这一差距，开发了一种靶向葡萄糖代谢的奥沙利铂（IV）-阿司匹林前药的聚（氨基酸）纳米制剂（NP/OXA-ASP），以通过抑制肿瘤糖酵解来改善化学免疫疗法。这种聚（氨基酸）纳米颗粒具有选择性释放功能，在还原条件下36小时内可释放90.0%的OXA-ASP。此外，超过80%的前药在12小时内转化为奥沙利铂和阿司匹林，促进线粒体损伤和糖酵解抑制，从而放大奥沙利铂诱导的免疫原性细胞死亡。此外，抑制糖酵解通量可减少乳酸泄漏，减轻免疫抑制性TME。这些机制共同促成了更强的化学免疫疗法疗效。与奥沙利铂加阿司匹林制剂相比，NP/OXA-ASP表现出卓越的性能，将肿瘤部位的乳酸水平降低了25.4%，将细胞毒性T淋巴细胞的比例提高了1.53倍，将调节性T细胞的比例降低了2.20倍，并将肿瘤抑制率提高了1.39倍。这些发现强调，NP/OXA-ASP是一个将肿瘤代谢调节与免疫调节相结合的有前景的平台，在推进临床化学免疫疗法方面具有巨大潜力。
