Dong Yuman, Li Jieru, Dai Yiwei, Zhang Xinyu, Wang Tao, Zhao Bin, Liu Wenbo, Chen Li, Yang Shaopei, Du Pengcheng, Jiao Zuoyi
Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China.
The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China.
Mater Today Bio. 2025 Jan 13;31:101487. doi: 10.1016/j.mtbio.2025.101487. eCollection 2025 Apr.
Immunotherapy, particularly immune checkpoint blockade (ICB), has opened the era of modern oncology, offering significant promise for modern oncology. However, the efficacy of immunotherapy is frequently curtailed by the immunosuppressive tumor microenvironment (ITM), a milieu shaped by tumor metabolic reprogramming. Herein, a novel tumor microenvironment-responsive nanocapsules (DNMCs) were developed that simultaneously modulate tumor metabolism and the ITM to enhance the effectiveness of chemo-immunotherapy. DNMCs consist of an acidic and redox-sensitive metal-organic framework (MOF) encapsulating Doxorubicin (DOX) and the indoleamine-2,3-dioxygenase1 (IDO1) inhibitor NLG919. In the tumor microenvironment, DNMCs degrade, rapidly releasing DOX and NLG919. DOX induces immunogenic cell death (ICD), while NLG919 regulates amino acid metabolism by modulating IDO1 activity, thereby reversing the immunosuppressive of ITM. Consequently, DNMCs elicit effective anti-tumor immune responses, characterized by an increased density of tumor-infiltrating CD8 cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing pancreatic cancer growth in KPC mice through combined chemo-immunotherapy. Overall, DNMCs exhibit significant tumor growth inhibition in pancreatic cancer patient-derived organoids (PDOs) and mouse models. This study presents a promising approach to enhancing chemo-immunotherapy by targeting tumor metabolic reprogramming and augmenting immune response against malignant tumors.
免疫疗法，尤其是免疫检查点阻断（ICB），开启了现代肿瘤学时代，为现代肿瘤学带来了巨大希望。然而，免疫疗法的疗效常常受到免疫抑制性肿瘤微环境（ITM）的限制，这是一种由肿瘤代谢重编程塑造的环境。在此，我们开发了一种新型的肿瘤微环境响应纳米胶囊（DNMCs），它能同时调节肿瘤代谢和ITM，以增强化学免疫疗法的效果。DNMCs由包裹着阿霉素（DOX）和吲哚胺-2,3-双加氧酶1（IDO1）抑制剂NLG919的酸性和氧化还原敏感金属有机框架（MOF）组成。在肿瘤微环境中，DNMCs降解，迅速释放DOX和NLG919。DOX诱导免疫原性细胞死亡（ICD），而NLG919通过调节IDO1活性来调节氨基酸代谢，从而逆转ITM的免疫抑制作用。因此，DNMCs引发有效的抗肿瘤免疫反应，其特征是肿瘤浸润性CD8细胞毒性T细胞密度增加以及免疫抑制性调节性T细胞（Tregs）减少，从而通过联合化学免疫疗法有效地抑制KPC小鼠的胰腺癌生长。总体而言，DNMCs在胰腺癌患者来源的类器官（PDOs）和小鼠模型中表现出显著的肿瘤生长抑制作用。这项研究提出了一种有前景的方法，即通过靶向肿瘤代谢重编程和增强对恶性肿瘤的免疫反应来增强化学免疫疗法。
