A Dihydroartemisinin-Loaded Nanoreactor Motivates Anti-Cancer Immunotherapy by Synergy-Induced Ferroptosis to Activate Cgas/STING for Reprogramming of Macrophage.

Infiltration of tumor-associated macrophages (TAM) characterized by an M2 phenotype is an overriding feature in malignant tumors. Reprogramming TAM is the most cutting-edge strategy for cancer therapy. In the present study, an iron-based metal framework (MOF) nanoreactor loaded with dihydroartemisinin (DHA) was developed, which provided high uptake by TAM and retains their viability, thus effectively addressing the inefficiency of the DHA at low concentrations. Impressively, DHA@MIL-101 could selectively accumulate in tumor tissues and remodel TAM to the M1 phenotype. The results of RNA sequencing further suggested that this nanoreactor may regulate ferroptosis, a DNA damage signaling pathway in TAM. Indeed, the outcomes confirmed that DHA@MIL-101 triggered ferroptosis in TAM. In addition, the findings revealed that DNA damage induced by DHA nanoreactors activated the intracellular cGAS sensor, resulting in the binding of STING to IRF3 and thereby up-regulating the immunogenicity. In contrast, blocking ferroptosis impaired DHA@MIL-101-induced activation of STING signaling and phenotypic remodeling. Finally, we showed that DHA nanoreactors deployed anti-tumor immunotherapy through ferroptosis-mediated TAM reprogramming. Taken together, we have achieved immune efficacy through TAM's remodeling by delivering DHA and iron ions into TAM using nanoreactors, providing a novel approach for combining phytopharmaceuticals with nanocarriers to regulate the immune microenvironment. This article is protected by copyright. All rights reserved.