AbstractInfiltration 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–organic framework (MOF) nanoreactor loaded with dihydroartemisinin (DHA) is developed, which provides high uptake by TAM and retains their viability, thus effectively addressing the inefficiency of the DHA at low concentrations. Impressively, DHA@MIL‐101 can selectively accumulate in tumor tissues and remodel TAM to the M1 phenotype. The results of RNA sequencing further suggest that this nanoreactor may regulate ferroptosis, a DNA damage signaling pathway in TAM. Indeed, the outcomes confirm that DHA@MIL‐101 triggers ferroptosis in TAM. In addition, the findings reveal that DNA damage induced by DHA nanoreactors activates the intracellular cGAS sensor, resulting in the binding of STING to IRF3 and thereby up‐regulating the immunogenicity. In contrast, blocking ferroptosis impairs DHA@MIL‐101‐induced activation of STING signaling and phenotypic remodeling. Finally, it is shown that DHA nanoreactors deploy anti‐tumor immunotherapy through ferroptosis‐mediated TAM reprogramming. Taken together, immune efficacy is achieved 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.