Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance.

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.

Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial-Mesenchymal Transition in an Ovarian Tumor.

Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against the treatment of OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve the therapeutic efficacy of olaparib against OVC is imperative. Our study identified tabersonine, a natural indole alkaloid, for its potential to increase the chemosensitivity of olaparib in OVC. The combined treatment of olaparib and tabersonine synergistically inhibited cell proliferation in OVC cells and suppressed tumor growth in A2780 xenografts. The combined treatment effectively suppressed epithelial-mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, and vimentin and induced DNA damage responses. Integrating quantitative proteomics, FHL1 was identified as a potential regulator to modulate EMT after tabersonine treatment. Increased expression of FHL1 was induced by tabersonine treatment, while downregulation of FHL1 reversed the inhibitory effects of tabersonine on OVC cells by mediating EMT. In vivo findings further reflected that the combined treatment of tabersonine and olaparib significantly inhibited tumor growth and OVC metastasis through upregulation of FHL1. Our findings reveal the role of tabersonine in improving the sensitivity of olaparib in OVC through FHL1-mediated EMT, suggesting that tabersonine holds promise for future application in OVC treatment.

Tabersonine enhances cisplatin sensitivity by modulating Aurora kinase A and suppressing epithelial-mesenchymal transition in triple-negative breast cancer.

CONTEXT: Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated. OBJECTIVE: This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP). MATERIALS AND METHODS: After tabersonine (10 µM) and/or CDDP (10 µM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes. RESULTS: Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 µM for BT549 and 27.0 µM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine. DISCUSSION AND CONCLUSIONS: Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.

Current understanding of plant-derived exosome-like nanoparticles in regulating the inflammatory response and immune system microenvironment.

Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.

The perceptions and experiences of caregivers of patients with dysphagia: A qualitative meta-synthesis.

AIMS: To understand the perceptions and experiences of family caregivers of adult patients with dysphagia. BACKGROUND: Dysphagia is a common symptom and burdens caregivers greatly. There is a growing body of studies concentrating on caregivers and caregiving experiences. However, no qualitative meta-synthesis has been conducted to explore the perceptions and experiences of family caregivers. DESIGN: A qualitative meta-ethnography. METHODS: A search was conducted for relevant articles in six electronic databases (PubMed, Web of Science, CINAHL, Ovid, Cochrane Library, ProQuest) and two Chinese databases (CNKI, Wanfang Data) from inception to February 2023. The Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) was used to evaluate study quality. The meta-ethnographic method was used to synthesize data from qualitative studies. The study was reported according to EQUATOR guidelines. RESULTS: Eleven studies were included and three themes emerged: (1) emotion and perception, (2) change and challenge (3) adaption and coping. CONCLUSION: This review highlighted the challenges and positive coping experienced by caregivers. Findings directly inform the development and implementation of supportive interventions to reduce caregivers' stress and promote adaptive coping. RELEVANCE TO CLINICAL PRACTICE: Pay attention to the needs of family caregivers of dysphagia. Family caregivers' perceived severity of dysphagia requires assessment. Caregivers need knowledge, support, and guidance to reduce their burden and fulfill their role.

Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis.

Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

High expression of six-transmembrane epithelial antigen of prostate 3 promotes the migration and invasion and predicts unfavorable prognosis in glioma.

Recent studies have suggested that ferroptosis, a form of iron-dependent regulated cell death, might play essential roles in tumor initiation and progression. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a ferrireductase involved in the regulation of intracellular iron homeostasis. However, the clinical significance and biological function of STEAP3 in human cancers remain poorly understood. Through a comprehensive bioinformatics analysis, we found that STEAP3 mRNA and protein expression were up-regulated in GBM, LUAD, and UCEC, and down-regulated in LIHC. Survival analysis indicated that STEAP3 had prognostic significance only in glioma. Multivariate Cox regression analysis revealed that high STEPA3 expression was correlated with poor prognosis. STEAP3 expression was significantly negatively correlated with promoter methylation level, and patients with lower STEAP3 methylation level had worse prognosis than those with higher STEAP3 methylation level. Single-cell functional state atlas showed that STEAP3 regulated epithelial-to-mesenchymal transition (EMT) in GBM. Furthermore, the results of wound healing and transwell invasion assays demonstrated that knocking down STEAP3 inhibited the migration and invasion of T98G and U251 cells. Functional enrichment analysis suggested that genes co-expressed with STEAP3 mainly participated in inflammation and immune-related pathways. Immunological analysis revealed that STEAP3 expression was significantly correlated with immune infiltration cells, including macrophages and neutrophils, especially the M2 macrophages. Individuals with low STEAP3 expression were more likely to respond to immunotherapy than those with high STEAP3 expression. These results suggest that STEAP3 promotes glioma progression and highlight its pivotal role in regulating immune microenvironment.

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma.

Finding biomarkers for immunotherapy is an urgent issue in cancer treatment. Cellular retinoic acid-binding protein 2 (CRABP2) is a controversial factor in the occurrence and development of human tumors. However, there is limited research on the relationship between CRABP2 and immunotherapy response. This study found that negative correlations of CRABP2 and immune checkpoint markers (PD-1, PD-L1, and CTLA-4) were observed in breast invasive carcinoma (BRCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). In particular, in SKCM patients who were treated with PD-1 inhibitors, high levels of CRABP2 predicted poor prognosis. Additionally, CRABP2 expression was elevated in cancer-associated fibroblasts (CAFs) at the single-cell level. The expression of CRABP2 was positively correlated with markers of CAFs, such as MFAP5, PDPN, ITGA11, PDGFRα/ß and THY1 in SKCM. To validate the tumor-promoting effect of CRABP2 in vivo, SKCM xenograft mice models with CRABP2 overexpression have been constructed. These models showed an increase in tumor weight and volume. Enrichment analysis indicated that CRABP2 may be involved in immune-related pathways of SKCM, such as extracellular matrix (ECM) receptor interaction and epithelial-mesenchymal transition (EMT). The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs. In conclusion, this study provides new insights into the role of CRABP2 in immunotherapy response. The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients. Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.

Dynamic m6A-ncRNAs association and their impact on cancer pathogenesis, immune regulation and therapeutic response.

Several types of modifications have been proven to participate in the metabolism and processing of different RNA types, including non-coding RNAs (ncRNAs). N-6-methyladenosine (m6A) is a dynamic and reversible RNA modification that is closely involved in the ncRNA homeostasis, and serves as a crucial regulator for multiple cancer-associated signaling pathways. The ncRNAs usually regulate the epigenetic modification, mRNA transcription and other biological processes, displaying enormous roles in human cancers. In this review, we summarized the significant implications of m6A-ncRNA interaction in various types of cancers. In particular, the interplay between m6A and ncRNAs in cancer pathogenesis and therapeutic resistance are being widely recognized. We also discussed the relevance of m6A-ncRNA interaction in immune regulation, followed by the interference on cancer immunotherapeutic procedures. In addition, we briefly highlighted the computation tools that could identify the accurate features of m6A methylome among ncRNAs. In summary, this review would pave the way for a better understanding of the biological functions of m6A-ncRNA crosstalk in cancer research and treatment.

Application of genomic selection and experimental techniques to predict cell death and immunotherapeutic efficacy of ferroptosis-related CXCL2 in hepatocellular carcinoma.

Since most hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages, there is no effective treatment to improve patient survival. Ferroptosis, a regulated cell death driven by iron accumulation and lipid peroxidation, has been reported to play an important role in tumorigenesis. However, the detailed mechanism and biological function of ferroptosis are still incompletely understood in HCC patients. In this study, we analyzed genomic profiles of three HCC datasets, GSE6764, GSE14520, and GSE14323. Venn diagrams were implemented to visualize the overlapping genes between differentially expressed genes and ferroptosis-related gene set. Then, one up-regulated gene, ACSL4, and five down-regulated genes, STEAP3, MT1G, GCH1, HAMP, and CXCL2, were screened. Based on the survival analysis performed by Kaplan-Meier plotter database, ferroptosis-related gene CXCL2 was demonstrated positively-correlated with the patients' prognosis. Moreover, CXCL2 overexpression significantly inhibited cell growth and improved cellular ROS, Fe2+ and MDA levels in HCC cells Huh7 and MHCC97H, suggesting the roles of CXCL2 in inducing ferroptotic cell death. In addition, aberrantly expressed CXCL2 was negatively associated with malignancy clinical features, such as nodal metastasis and higher grades. The ssGSEA enrichment analysis revealed that CXCL2 co-expressed molecules were mainly involved in inflammation and immune-related pathways, such as acute inflammatory response, humoral immune response, adaptive immune response. TISIDB algorithm indicated the positive correlation between CXCL2 expression and tumor-infiltrating immune cells, including neutrophils and macrophages. Additionally, we also found that CXCL2 was positively correlated with immune infiltration score, and HCC patients with higher score harbored better prognosis. Together, these findings suggested that CXCL2 may enhance ferroptosis sensitivity and regulate immune microenvironment in HCC, and serve as a promising prognosis biomarker for HCC patients.