The toxic effect of Polystyrene Microplastics (PS-MPs) on leydig cells were found in male mice, but the toxic mechanism was not clear. The PS-MPs exposure mice model and cell model were established in this study to explore the leydig cells toxic mechanism. In vivo study, the leydig cells toxicity in male mice was evaluated exposed to PS-MPs for 28 days. And found that the sperm density, mobility and testosterone (T) level decreased, and the sperm malformation rate and malondialdehyde level increased. PS-MPs exposure impaired the function of male reproduction. The results also showed that the levels of testosterone-producing proteins (StAR, P450scc,3β-HSD and CYP17A1) decreased, apoptosis signaling pathways (Bax/Bcl-2, Caspase-8 and Caspase-12) were activated and endoplasmic reticulum stress (GRP78/p-PERK/CHOP) occurred in male mice exposed to PS-MPs. In vitro study, TM3 cells (leydig cells) were treated with 50, 100 and 200 μg/mL of PS-MPs for 24 h. And we found that PS-MPs exposure reduced the cell viability and the level of T, increased reactive oxygen species (ROS) level in TM3 cells. PS-MPs exposure impaired the function of the leydig cells. Further testing revealed that PS-MPs could activate GRP78/p-PERK/CHOP pathway, aggrandized endoplasmic reticulum stress in the leydig cells, then increased apoptosis level, and induced testosterone synthase protein reduction. These could be reversed when exposed to ROS inhibitor or endoplasmic reticulum stress inhibitor. In conclusion, PS-MPs exposure induced the high level of ROS, activated the GRP78/p-PERK/CHOP signaling pathway, enhanced endoplasmic reticulum stress in leydig cells, then apoptosis level increased, which impaired the leydig cell function.
Dying tumor cells regulated by immunogenic cell death (ICD) inducers are promising candidates for cancer vaccine development because of their comprehensive antigen spectrum. However, their limited immunogenicity and potential tumorigenicity hinder clinical translation. To address these challenges, a nano-orchestrator is developed that targets the endoplasmic reticulum (ER) stress, a critical pre-ICD event, to optimize the “precise dose” of ER stress. Using a clinical-range irradiation fluence (50‒200 J cm −2 ) with an 808 nm laser, the release of damage associated molecular patterns (DAMPs) and antigens are precisely regulated. A fluence of 150 J cm −2 (2 W cm −2 for 75 s) increases dendritic cell maturation and antitumor T cell proliferation, providing valuable clinical insights. The ER stress nano-orchestrator enhances both adjuvanticity and antigenicity via the protein kinase R-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP) pathway to regulate ICD-induced DAMPs and promote tumor cell apoptosis. These optimized ER stress phototherapeutic dying tumor cells can serve as prophylactic vaccines, achieving a remarkable 100% success rate against tumor rechallenge in vivo. Additionally, the nano-orchestrator shows the potential to develop in situ therapeutic tumor vaccines when combined with anti-PD-L1 treatment, providing important insights into enhancing the efficacy of immune checkpoint regulators by modulating endogenous immune responses.
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