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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.

Additional file 1: Figure S1. Size distribution of MIL-101-NH2, hydrodynamic diameters and stability evaluation of DHA@MIL-101. Figure S2. UV–vis absorption spectra of DHA, MIL-101-NH2 and DHA@MIL-101-NH2. Figure S3. TGA curves of MIL-101-NH2 and DHA@MIL-101-NH2. Figure S4. SEM images of ICN-DHA@MIL-101. Figure S5. UV–vis absorption spectra of ICG and ICG-DHA@MIL-101-NH2. Figure S6 Uptake of ICG-DHA@MIL-101 in LLC. Figure S7. DHA up-regulated the expression of TfR1 in LLC. Figure S8. DHA@MIL-101 promoted Nuclear translocation of NF-κB of LLC. Figure S9. DHA@MIL-101 promoted phosphorylation of NF-κB of LLC. Figure S10. The ICG-DHA@MIL-101 distribution in tumor grafts. Figure S11. The COX-2 and γ-H2A.X expression in tumor grafts. Figure S12. DHA@MIL-101 induced prominent apoptosis and necrosis of cancer cells in tumor grafts. Figure S13. DHA@MIL-101 promoted the expression of Bax, caspase-3, decreased expression of PCNA in tumor grafts. Figure S14. The body weight of LLC-bearing mice varied little after DHA@MIL-101 treatment. Figure S15. No evident organ toxicity in DHA@MIL-101-treated mice. Figure S16. LPO in LLC was detected using C11-BODIPY probe with confocal microscopy. Figure S17. Quantitative gray analysis of WB results in Fig. 2 to Fig. 4.

The present work aims to prove the concept of tumor-targeted drug delivery mediated by platelets. Doxorubicin (DOX) attached to nanodiamonds (ND-DOX) was investigated as the model payload drug of platelets. In vitro experiments first showed that ND-DOX could be loaded in mouse platelets in a dose-dependent manner with a markedly higher efficiency and capacity than free DOX. ND-DOX-loaded platelets (Plt@ND-DOX) maintained viability and ND-DOX could be stably held in the platelets for at least 4 hr. Next, mouse Lewis lung cancer cells were found to activate Plt@ND-DOX and thereby stimulate cargo unloading of Plt@ND-DOX. The unloaded ND-DOX was taken up by co-cultured cancer cells which consequently exhibited loss of viability, proliferation suppression and apoptosis. In vivo, Plt@ND-DOX displayed significantly prolonged blood circulation time over ND-DOX and DOX in mice, and Lewis tumor grafts demonstrated infiltration, activation and cargo unloading of Plt@ND-DOX in the tumor tissue. Consequently, Plt@ND-DOX effectively reversed the growth of Lewis tumor grafts which exhibited significant inhibition of cell proliferation and apoptosis. Importantly, Plt@ND-DOX displayed a markedly higher therapeutic potency than free DOX but without the severe systemic toxicity associated with DOX. Our findings are concrete proof of platelets as efficient and efficacious carriers for tumor-targeted nano-drug delivery with the following features: 1) large loading capacity and high loading efficiency, 2) good tolerance of cargo drug, 3) stable cargo retention and no cargo unloading in the absence of stimulation, 4) prolonged blood circulation time, and 5) excellent tumor distribution and tumor-activated drug unloading leading to high therapeutic potency and few adverse effects. Platelets hold great potential as efficient and efficacious carriers for tumor-targeted nano-drug delivery.

Gonococcal conjunctivitis is due to ophthalmic infection with Neisseria gonorrhoeae, and it is considered rare in the non-neonatal populations, particularly its association with gonorrhea and chlamydial urethritis in the same patient. Here we describe a 27-year-old newly married man presenting gonococcal conjunctivitis and discuss the selection of antibiotic drugs associated with its course.

Additional file 1: Extended Data Figure S1. Evodiamine can inhibit growth and induce apoptosis of NSCLC cells. Extended Data Figure S2. Evodiamine inactivates the PD-L1 promoter. Extended Data Figure S3. MUC1-C inhibition can diminish the PD-L1 expression and decrease the apoptosis levels of CD8+T cells. Extended Data Figure S4. Evodiamine potentiates the anti-tumor activity of CD8+ T cells in vivo. Extended Data Figure S5. Combination Evodiamine and PD-1 mAb treatment can enhance tumor growth control and survival of Lewis lung carcinoma model. Extended Data Figure S6. MUC1-C is a potential novel mechanism of evodiamine of tumor inhibition.