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-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.

Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy.

BACKGROUND: The immunosuppressive microenvironment of lung cancer serves as an important endogenous contributor to treatment failure. The present study aimed to demonstrate the promotive effect of DHA on immunogenic cell death (ICD) in lung cancer as well as the mechanism. METHODS: The lewis lung cancer cells (LLC), A549 cells and LLC-bearing mice were applied as the lung cancer model. The apoptosis, ferroptosis assay, western blotting, immunofluorescent staining, qPCR, comet assay, flow cytometry, confocal microscopy, transmission electron microscopy and immunohistochemistry were conducted to analyze the functions and the underlying mechanism. RESULTS: An increased apoptosis rate and immunogenicity were detected in DHA-treated LLC and tumor grafts. Further findings showed DHA caused lipid peroxide (LPO) accumulation, thereby initiating ferroptosis. DHA stimulated cellular endoplasmic reticulum (ER) stress and DNA damage simultaneously. However, the ER stress and DNA damage induced by DHA could be abolished by ferroptosis inhibitors, whose immunogenicity enhancement was synchronously attenuated. In contrast, the addition of exogenous iron ions further improved the immunogenicity induced by DHA accompanied by enhanced ER stress and DNA damage. The enhanced immunogenicity could be abated by ER stress and DNA damage inhibitors as well. Finally, DHA activated immunocytes and exhibited excellent anti-cancer efficacy in LLC-bearing mice. CONCLUSIONS: In summary, the current study demonstrates that DHA triggers ferroptosis, facilitating the ICD of lung cancer thereupon. This work reveals for the first time the effect and underlying mechanism by which DHA induces ICD of cancer cells, providing novel insights into the regulation of the immune microenvironment for cancer immunotherapy by Chinese medicine phytopharmaceuticals.

Chlorin e6-induced photodynamic effect facilitates immunogenic cell death of lung cancer as a result of oxidative endoplasmic reticulum stress and DNA damage.

Suppression of the immune microenvironment is an important endogenous contributor to treatment failure in lung cancer. Photodynamic therapy (PDT) is widely used in the treatment of malignant tumors owing to its photo-selectivity and minimal side effects. Some studies have shown the ability of photodynamic action not only to cause photo-cytotoxicity to tumor cells but also to induce immunogenic cell death (ICD). However, the mechanism by which PDT enhances tumor immunogenicity is poorly understood. The present study aimed to explore the immunogenicity effect of PDT on lung cancer and to reveal the underlying mechanism. First, we searched for effective conditions for PDT-induced apoptosis in lung cancer cells. Just as expected, chlorin e6 (Ce6) PDT could enhance the immunogenicity of lung cancer cells alongside the induction of apoptosis, characterized by up-regulation of CRT, HSP90, HMGB1 and MHC-I. Further results showed the generation of ROS by Ce6 PDT under the above conditions, which is an oxidative damaging agent. Simultaneously, PDT induced endoplasmic reticulum (ER) stress in cells, as evidenced by enhanced Tht staining and up-regulated CHOP and GRP78 expression. Moreover, PDT led to DNA damage response (DDR) as well. However, the redox inhibitor NAC abolished the ER stress and DDR caused by PDT. More importantly, NAC also attenuated PDT-induced improvement of immunogenicity in lung cancer. On this basis, the PDT-induced CRT up-regulation was found to be attenuated in response to inhibition of ER stress. In addition, PDT-induced increase in HMGB1 and HSP90 release was blocked by inhibition of DDR. In summary, Ce6 PDT could produce ROS under certain conditions, which leads to ER stress that promotes CRT translocation to the cell membrane, and the resulting DNA damage causes the expression and release of nuclear HMGB1 and HSP90, thereby enhancing the immunogenicity of lung cancer. This current study elucidates the mechanism of PDT in ameliorating the immunogenicity of lung cancer, providing a rationale for PDT in regulating the immune microenvironment for the treatment of malignant tumors.

Dihydroartemisinin remodels macrophage into an M1 phenotype via ferroptosis-mediated DNA damage.

Lung cancer recruits tumor-associated macrophages (TAMs) massively, whose predominantly pro-tumor M2 phenotype leads to immunosuppression. Dihydroartemisinin (DHA) has been proven to remodel TAM into an anti-tumor M1 phenotype at certain concentrations in the present study, which was hypothesized to facilitate anti-lung cancer immunotherapy. However, how DHA remodels the TAM phenotype has not yet been uncovered. Our previous work revealed that DHA could trigger ferroptosis in lung cancer cells, which may also be observed in TAM thereupon. Sequentially, in the current study, DHA was found to remodel TAM into the M1 phenotype in vitro and in vivo. Simultaneously, DHA was observed to trigger ferroptosis in TAM and cause the DNA damage response and NF-κB activation. Conversely, the DHA-induced DNA damage response and NF-κB activation in TAM were attenuated after the inhibition of ferroptosis in TAM using an inhibitor of ferroptosis. Importantly, a ferroptosis inhibitor could also abolish the DHA-induced phenotypic remodeling of TAM toward the M1 phenotype. In a nutshell, this work demonstrates that DHA-triggered ferroptosis of TAM results in DNA damage, which could activate downstream NF-κB to remodel TAM into an M1 phenotype, providing a novel strategy for anti-lung cancer immunotherapy. This study offers a novel strategy and theoretical basis for the use of traditional Chinese medicine monomers to regulate the anti-tumor immune response, as well as a new therapeutic target for TAM phenotype remodeling.

A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin.

BACKGROUND: Chemodynamic therapy (CDT) relying on intracellular iron ions and H2O2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H2O2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H2O2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy. RESULTS: The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity. CONCLUSION: In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine.

Norovirus outbreaks in Fengtai District, Beijing, China, 2014.

Norovirus (NoV) is the most common cause of non-bacterial acute gastroenteritis (AGE) outbreaks worldwide. Eight NoV outbreaks in the Fengtai District of Beijing City, China, were identified in 2014. Samples were collected from the eight outbreaks, and 73 out of 119 samples from cases and 10 out of 59 samples from the close contacts were positive for NoVs. The genotypes were determined by sequencing analysis. Six different GII genotypes, including GII.2, 4, 6, 7, 8, 14, and 17 were found, and GII.4 was not the local major epidemic genotype in the present study. Enhanced strain surveillance is necessary for future NoV epidemics.

Outbreak of febrile illness caused by coxsackievirus A4 in a nursery school in Beijing, China.

BACKGROUND: Coxsackievirus A4 (CV-A4) is classified as human enterovirus A according to its serotype. CV-A4, an etiological agent of hand, foot, and mouth disease, affects children worldwide and can circulate in closed environments such as schools and hospitals for long periods. FINDINGS: An outbreak of febrile illness at a nursery school in Beijing, China, was confirmed to be caused by CV-A4. Phylogenetic analysis of the complete genome of the isolated strain showed that the virus belongs to the same cluster as the predominant CV-A4 strain in China. This outbreak was controlled by effective measures. CONCLUSIONS: The early identification of the pathogen and timely intervention may be the most critical factors in controlling an outbreak caused by CV-A4 in a preschool.