Han Min, Zhou Shiying, Liao Zunde, Zishan Chen, Yi Xiangting, Wu Chuanbin, Zhang Dongmei, He Yao, Leong Kam W, Zhong Yiling
College of Pharmacy, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, Guangdong, 511443, China.
College of Pharmacy, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, Guangdong, 511443, China.
Biomaterials. 2025 Apr;315:122934. doi: 10.1016/j.biomaterials.2024.122934. Epub 2024 Oct 30.
Immunotherapy has transformed cancer treatment, but its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME), which are predominantly influenced by the metabolism of cancer cells. Among these metabolic pathways, the indoleamine 2,3-dioxygenase (IDO) pathway is particularly crucial, as it significantly contributes to TME suppression and influences immune cell activity. Additionally, inducing immunogenic cell death (ICD) in tumor cells can reverse the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy. Herein, we develop CGDMRR, a novel bimetallic peroxide-based nanodrug based on copper-cerium peroxide nanoparticles. These nanotherapeutics are engineered to mitigate tumor hypoxia and deliver therapeutics such as 1-methyltryptophan (1MT), glucose oxidase (GOx), and doxorubicin (Dox) in a targeted manner. The design aims to alleviate tumor hypoxia, reduce the immunosuppressive effects of the IDO pathway, and promote ICD. CGDMRR effectively inhibits the growth of 4T1 tumors and elicits antitumor immune responses by leveraging immunometabolic interventions and therapies that induce ICD. Furthermore, when CGDMRR is combined with a clinically certified anti-PD-L1 antibody, its efficacy in inhibiting tumor growth is enhanced. This improved efficacy extends beyond unilateral tumor models, also affecting bilateral tumors and lung metastases, due to the activation of systemic antitumor immunity. This study underscores CGDMRR's potential to augment the efficacy of PD-L1 blockade in breast cancer immunotherapy.
免疫疗法已经改变了癌症治疗方式，但其疗效常常受到肿瘤微环境（TME）免疫抑制特性的限制，而肿瘤微环境主要受癌细胞代谢的影响。在这些代谢途径中，吲哚胺2,3-双加氧酶（IDO）途径尤为关键，因为它对TME抑制有显著作用，并影响免疫细胞活性。此外，诱导肿瘤细胞发生免疫原性细胞死亡（ICD）可以逆转免疫抑制性TME，从而提高免疫疗法的疗效。在此，我们开发了CGDMRR，一种基于过氧化铜铈纳米颗粒的新型双金属过氧化物纳米药物。这些纳米治疗剂经过设计，可减轻肿瘤缺氧状况，并以靶向方式递送诸如1-甲基色氨酸（1MT）、葡萄糖氧化酶（GOx）和阿霉素（Dox）等治疗药物。其设计目的是缓解肿瘤缺氧、降低IDO途径的免疫抑制作用并促进ICD。CGDMRR通过利用诱导ICD的免疫代谢干预和疗法，有效抑制4T1肿瘤的生长并引发抗肿瘤免疫反应。此外，当CGDMRR与临床认证的抗PD-L1抗体联合使用时，其抑制肿瘤生长的疗效会增强。由于激活了全身抗肿瘤免疫，这种提高的疗效不仅适用于单侧肿瘤模型，对双侧肿瘤和肺转移瘤也有效果。这项研究强调了CGDMRR在增强乳腺癌免疫治疗中PD-L1阻断疗效方面的潜力。
