Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression

Plant-derived nanovesicles (PDNVs) have been proposed as a major mechanism for inter-kingdom interaction and communication, but the effector components enclosed and the mechanisms involved are largely unknown. The plant Artemisia annua , known for its anti-malaria properties, exhibits a wide range of biological activities including the immunoregulatory and anti-tumor properties with the mechanisms to be further addressed. Here, we isolated and purified the exosome-like particles from Artemisia annua , and characterized them as nano-scaled and membrane-bound, which were therefore termed artemisia-derived nanovesicles (ADNVs). Remarkably, the vesicles displayed a potential to inhibit tumor growth and boost anti-tumor immunity, primarily through remolding tumor microenvironment and reprogramming tumor-associated macrophages (TAMs). More importantly, we identified plant-derived mitochondrial DNA (mtDNA), upon internalized into TAMs via the vesicles, as a major effector mechanism to induce the cGAS-STING pathway driving the shift of pro-tumor macrophages to anti-tumor phenotype. Furthermore, our data showed that administration of ADNVs greatly improved the efficacy of PD-L1 inhibitor, a prototypic immune checkpoint inhibitor (ICI), in a murine lung cancer model. Together, the present study, for the first time, to our knowledge, unravels an inter-kingdom interaction wherein medical plant-derived mtDNA, via the nanovesicles, induces the immunostimulatory signaling in mammal immune cells for resetting anti-tumor immunity.