Li Songyan, Ma Zilin, Zhao Yilei, Yan Jie, Wang Xuechun, Zhao Wen, Jiao Jianwei, Duan Xiuying, Zhang Guiqiang
Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
Mater Today Bio. 2025 Apr 23;32:101799. doi: 10.1016/j.mtbio.2025.101799. eCollection 2025 Jun.
Reprogramming the metabolism-mediated tumor microenvironment is a promising strategy to revitalize antitumor immunity. However, single metabolic modulation is often insufficient to achieve significant antitumor effects due to the intricate metabolic mechanisms in tumors. This study fabricated dual metabolism-disrupted carrier-free nanoparticles (LN NPs) copper coordination-driven assembly of a glycolysis inhibitor and an indoleamine-pyrrole 2,3-dioxygenase 1 inhibitor. After intravenous administration, LN NPs effectively accumulated at tumor sites to enhance the bioavailability of therapeutic agents. They simultaneously disrupted glycolysis and amino acid metabolism, resulting in a reduction in the levels of inhibitory metabolites and alleviating tumor immunosuppression. Furthermore, the inhibition of glycolysis generating reactive oxygen species, and copper-triggered cuproptosis synergistically induced potent immunogenic cell death. Subsequently, LN NPs elicited a robust cascade of immunological responses that effectively inhibited tumor growth and metastasis. Overall, this study offered a promising paradigm for tumor treatment via the synergistic dual metabolic modulation and cuproptosis immunotherapy.
重编程代谢介导的肿瘤微环境是重振抗肿瘤免疫的一种有前景的策略。然而，由于肿瘤中复杂的代谢机制，单一的代谢调节往往不足以实现显著的抗肿瘤效果。本研究制备了双代谢破坏的无载体纳米颗粒（LN NPs），通过铜配位驱动组装糖酵解抑制剂和吲哚胺-吡咯2,3-双加氧酶1抑制剂。静脉注射后，LN NPs有效地在肿瘤部位蓄积，以提高治疗药物的生物利用度。它们同时破坏糖酵解和氨基酸代谢，导致抑制性代谢物水平降低，减轻肿瘤免疫抑制。此外，糖酵解产生的活性氧的抑制以及铜触发的铜死亡协同诱导强烈的免疫原性细胞死亡。随后，LN NPs引发了强大的免疫反应级联，有效抑制肿瘤生长和转移。总体而言，本研究通过协同双代谢调节和铜死亡免疫疗法为肿瘤治疗提供了一种有前景的范例。
