Chen Heying, Wang Dongqing, Liu Jiahe, Chen Jun, Hu Yi, Ni Yilu
The Key Laboratory of Chinese Ministry of Education in Laboratory Medical Diagnostics, College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
ACS Appl Mater Interfaces. 2025 Mar 5;17(9):13375-13390. doi: 10.1021/acsami.4c18570. Epub 2025 Feb 18.
The specific activation of dendritic cells (DCs) and tumor-associated macrophages (TAMs) can activate innate and adaptive immune responses to reverse the tumor immunosuppressive microenvironment. In this study, manganese ferrite nanohybrid MnFeO@(M1M-DOX) is synthesized to activate cGAS-STING and NF-κB crosstalk in DCs and TAMs. MnFeO, as the source of Fe/Fe and Mn, is encapsulated with a microdose of doxorubicin (DOX) using an M1 macrophage cytomembrane. Fe/Fe and DOX can cooperatively induce tumorous ferroptosis, triggering immunogenic cell death (ICD) that exposes tumor antigens. The release of Fe/Fe and Mn has intrinsic dual-immunomodulatory effects on the activation of DCs and the reprogramming of TAMs from the M2 to M1 phenotype. Briefly, Fe/Fe activates the NF-κB signaling pathway to trigger the activation of STING signaling. Meanwhile, Mn further enhances the activation of STING and stimulates NF-κB in a cascade-activating manner. Thus, the mutually reinforcing dual activation of cGAS-STING and NF-κB crosstalk prompts the strong maturation of DCs and TAMs, synergistically promoting the infiltration of T cells to inhibit primary tumor growth and localized recurrence. This work proposes a strategy for delivering immunomodulatory metal ions in nanoalloy and harnessing the activation of multisignaling pathways in antigen-presenting cells (APCs) to provide perspectives for tumor immunotherapy.
树突状细胞（DCs）和肿瘤相关巨噬细胞（TAMs）的特异性激活可激活先天性和适应性免疫反应，以逆转肿瘤免疫抑制微环境。在本研究中，合成了锰铁氧体纳米杂化物MnFeO@(M1M-DOX)，以激活DCs和TAMs中的cGAS-STING和NF-κB串扰。MnFeO作为Fe/Fe和Mn的来源，使用M1巨噬细胞膜包裹微量阿霉素（DOX）。Fe/Fe和DOX可协同诱导肿瘤性铁死亡，触发暴露肿瘤抗原的免疫原性细胞死亡（ICD）。Fe/Fe和Mn的释放对DCs的激活以及TAMs从M2表型重编程为M1表型具有内在的双重免疫调节作用。简而言之，Fe/Fe激活NF-κB信号通路以触发STING信号的激活。同时，Mn进一步增强STING的激活，并以级联激活方式刺激NF-κB。因此，cGAS-STING和NF-κB串扰的相互增强的双重激活促使DCs和TAMs强烈成熟，协同促进T细胞浸润以抑制原发性肿瘤生长和局部复发。这项工作提出了一种在纳米合金中递送免疫调节金属离子并利用抗原呈递细胞（APC）中多信号通路激活的策略，为肿瘤免疫治疗提供了思路。
