Tumor Microenvironment-Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma.

Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR-Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.

Research progress on hydrogel-based drug therapy in melanoma immunotherapy.

Melanoma is one of the most aggressive skin tumors, and conventional treatment modalities are not effective in treating advanced melanoma. Although immunotherapy is an effective treatment for melanoma, it has disadvantages, such as a poor response rate and serious systemic immune-related toxic side effects. The main solution to this problem is the use of biological materials such as hydrogels to reduce these side effects and amplify the immune killing effect against tumor cells. Hydrogels have great advantages as local slow-release drug carriers, including the ability to deliver antitumor drugs directly to the tumor site, enhance the local drug concentration in tumor tissue, reduce systemic drug distribution and exhibit good degradability. Despite these advantages, there has been limited research on the application of hydrogels in melanoma treatment. Therefore, this article provides a comprehensive review of the potential application of hydrogels in melanoma immunotherapy. Hydrogels can serve as carriers for sustained drug delivery, enabling the targeted and localized delivery of drugs with minimal systemic side effects. This approach has the potential to improve the efficacy of immunotherapy for melanoma. Thus, the use of hydrogels as drug delivery vehicles for melanoma immunotherapy has great potential and warrants further exploration. [BMB Reports 2024; 57(2): 71-78].

Cotton miR393-TIR1 Module Regulates Plant Defense Against Verticillium dahliae via Auxin Perception and Signaling.

Plant auxin is essential in plant growth and development. However, the molecular mechanisms of auxin involvement in plant immunity are unclear. Here, we addressed the function of the cotton (Gossypium hirsutum) miR393-TIR1 module in plant defense against Verticillium dahliae infection via auxin perception and signaling. GhTIR1 was directedly cleaved by ghr-miR393 according to mRNA degradome data, 5'-RACE analysis, and a GUS reporter assay. Ghr-miR393 knockdown significantly increased plant susceptibility to V. dahliae compared to the control, while ghr-miR393 overexpression and GhTIR1 knockdown significantly increased plant resistance. External indole-3-acetic acid (IAA) application significantly enhanced susceptibility to V. dahliae in ghr-miR393 knockdown and control plants compared to mock treatment, and only slightly increased susceptibility in overexpressing ghr-miR393 and GhTIR1-silenced plants. Application of external PEO-IAA (an auxin antagonist) had a contrary trend with IAA application. Based on yeast two-hybrid and bimolecular fluorescence complementation assays, GhTIR1 interacted with GhIAA14 in the nucleus, and GhIAA14 knockdown reduced plant resistance to V. dahliae infection. The results suggested that the ghr-miR393-GhTIR1 module regulates plant defense via auxin perception and signaling. Additionally, simultaneous knockdown of GhTIR1 and GhICS1 significantly increased plant susceptibility to V. dahliae compared to the control, indicating that salicylic acid (SA) accumulation is vital for the ghr-miR393-GhTIR1 module to regulates plant resistance. Transcriptome data also demonstrated that GhTIR1 knockdown significantly downregulated expression of auxin-related genes and upregulated expression of SA-related genes. Overall, the ghr-miR393-GhTIR1 module participates in plant response to V. dahliae infection via IAA perception and signaling partially depending on the SA defense pathway.