In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints. Finally, predictions are made for future personalized cancer immunotherapy based on different checkpoint modulations.

We explored the therapeutic efficacy of Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) and its inhibition of the functions of dendritic cells (DCs) in dry eye disease (DED). MSC-EVs were isolated from the culture supernatants of mesenchymal stromal cells (MSCs) and characterized. In vitro, human corneal epithelial cells (HCECs) were cultured in hyperosmotic medium to simulate the DED hyperosmotic environment and treated with MSC-EVs. Cell viability was assessed, and the expression of inflammatory cytokines was quantified. Next, we induced DED in female C57BL/6 mice and divided the mice into groups treated with either MSC-EVs or phosphate buffer solution (PBS) eye drops. Disease severity was assessed; mRNA expression of inflammatory cytokines was analyzed by RT-PCR; and Th17 cells were detected by flow cytometry. Lastly, we evaluated DCs by immunofluorescence and flow cytometric analysis to assess its amounts and maturation. MSC-EVs showed protective effects on HCECs under hyperosmotic stress in vitro, suppressing the expression of inflammatory cytokines. In vivo, mice topically treated with MSC-Evs presented reduced DED disease severity compared to PBS-treated mice. MSC-Evs downregulated the expression of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, as well as the frequency of Th17 cells. Further investigation showed that MSC-EVs suppressed the increase of amounts and the maturation of DCs in DED. Changes of morphological characters of DCs were also inhibited by MSC-EVs. Our study revealed that MSC-EVs suppressed ocular surface inflammation by inhibiting DCs activation-mediated Th17 immune responses, explicating the therapeutic potential of MSC-EVs in DED and other ocular surface diseases.

This study aims to explore the therapeutic efficacy of evodiamine (EVO) in the treatment of dry eye disease (DED). Mouse models of DED was developed using benzalkonium chloride eye drops and subcutaneous atropine injections. Corneal epithelial defects were assessed by fluorescein sodium staining, and tear secretion was measured with the phenol red thread test. For the in vitro model, human corneal epithelial cells were cultured in a sodium chloride-enriched medium. Phenotypic and mechanistic analyses were conducted using real-time quantitative PCR, Western blotting, flow cytometry, and immunofluorescence staining. The administration of EVO eye drops significantly enhanced tear secretion in mice, ameliorated ocular surface damage, decreased the expression of corneal inflammatory factors, and increased the density of conjunctival goblet cells. Furthermore, EVO reduced oxidative stress by promoting autophagy. Mechanistically, EVO-induced autophagy was mediated via the p53/mammalian target of rapamycin pathway. These findings suggest that EVO is a potential therapeutic agent for the treatment of DED, with its beneficial effects attributed to the activation of autophagy through the p53/mammalian target of rapamycin pathway.

About 10.2 % of people worldwide suffer from pterygium, a proliferative disorder marked by a wing-shaped growth that stretches from corneoscleral limbus to central area. MER proto-oncogene tyrosine kinase (MERTK) has been linked in recent research to the promotion of organ fibrosis and tumor growth. To look into its underlying function and mechanisms, we employed RNA-sequencing methods, MERTK inhibitors, and a series of tests. Primary human pterygium fibroblasts (HPFs) and pterygium tissues both exhibited high expression of MERTK. HPFs' migratory and proliferative capabilities were decreased by MERTK inhibition, which also encouraged an increase in apoptosis. Cell cycle arrest was mechanistically caused by MERTK inhibition. Additionally, further research revealed that this was linked to the downregulation of the ERK/p38 MAPK and PI3K/AKT signaling pathways In addition, MERTK expression was positively correlated with clinical grading, which indicates the degree of pterygium fibrosis. Collectively, targeting MERTK presents a potential therapeutic strategy to limit the proliferation, migration, and fibrosis associated with pterygium. This research may pave a promising way for more effective therapeutic approaches at controlling disease progression.