Zhihai Qin

Lung metastasis remains a determinant of poor prognosis and survival in breast cancer and is understood to depend on a permissive pulmonary immune niche ra

Retraction: Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor

Cholangiocarcinoma (CCA), the second most prevalent primary hepatic malignancy, demonstrates resistance to antiangiogenic therapy due possibly to the dynam

Rationale: mRNA vaccine-based cancer immunotherapy requires innate immune activation followed by potent cellular immunity. Vectors of lipid nanoparticles (LNPs) with proinflammatory properties activate the innate immune pathway, while excessive inflammatory response of mRNA-LNPs vaccine often results in systemic inflammation, compromising its therapeutic safety.

Zinc is an essential trace metal in the human body, playing a crucial role in various biological processes. It exists in 2 forms in cells: “bound” and “labile,” depending on its affinity with ligands. Zinc homeostasis is tightly regulated by zinc transporters, including the ZIP and ZnT protein families. However, zinc dyshomeostasis has been observed in various cancers, including breast cancer, pancreatic cancer, and hepatocellular carcinoma. Recent studies indicate that the zinc content in blood and tumor tissues can either increase or decrease, whereas specific zinc transporters may be upregulated or downregulated. Zinc dysregulation in cancer cells, as well as in immune cells and non-immune stromal cells, potentially affects the cell cycle, apoptosis, metabolism, immunity, and treatment resistance. Although many reviews have discussed zinc homeostasis under physiological conditions, few have explores its role in cancer pathology. We conducted a literature search on PubMed and Google Scholar using the keywords “tumor,” “zinc levels,” and “zinc transporter,” excluding outdated articles and those lacking full-text access. Among similar studies, we selected articles with more recent publication dates and larger sample sizes. In this review, we summarize recent advances in the study of zinc in tumors, highlighting studies on abnormal zinc levels and zinc transporters in various cancers. We also explore the effects of zinc dysregulation, its potential mechanisms, and the emerging concept that zinc dyshomeostasis may be a hallmark of cancer.

Extrahepatic cholangiocarcinoma (eCCA) is a rare but refractory cancer with dense desmoplasia. Prognosis-associated stromal cells in eCCA remain poorly characterized. Here, we profiled the tumor cellular composition and identified prognosis-related stromal signatures by single-cell RNA sequencing (scRNA-seq) in eCCA. ECCA patients were further stratified into different categories based on identified stromal signatures. Using scRNA-seq, we profiled the transcriptomes of 37,498 individual cells from eight eCCA biopsies, including five tumor tissues and three paired adjacent normal tissues. Bulk RNA sequencing (bRNA-seq) was also performed on 43 eCCA tumor tissues. Stromal cell composition and heterogeneity were examined through differential gene expression and gene set enrichment analyses. By assessing the expression levels of marker genes in bRNA-seq data, the correlation of stromal cell clusters with survival was explored. The GSVA scores of the cell-specific signature genes of the prognosis-related stromal cell subtypes were calculated and used to stratify eCCA patients. The results revealed that tumor stroma in eCCA were composed of hematopoietic progenitor-like cells (HPLCs), fibroblasts (Fb), Schwann cells (Sch), endothelial cells and immune cells. Prognosis-associated stromal cell subpopulations included MKI67 + HPLC, TMEM158 + C3-Fb, FOXP3 + regulatory T cells (Treg), SLIT2 + Sch, TPSD1 + C2-mast cells (MC) and CTSG + C3-MC. Based on these stromal signatures, the eCCA tumors were categorized into three classes: proliferative Group 1 with enrichment of MKI67 + HPLC, inflammatory and fibrotic Group 2 with enrichment of TPSD1 + C2- MC, FOXP3 + Treg and TMEM158 + C3-Fb, and neuronal Group 3 with enrichment of SLIT2 + Sch and CTSG + C3-MC. ECCA patients in Group 3 had a better prognosis when compared to Group 1 and 2, reflecting different impact of stromal subtypes on tumor progression. Single-cell transcriptomic analysis reveals prognosis-related stromal signatures that potentiate the stratification of eCCA into proliferative, inflammatory and fibrotic, and neuronal phenotypes, which has important implications on molecular classification and exploring therapeutic targets in eCCA.

Lipid nanoparticles (LNPs)‐based mRNA vaccines have witnessed their great advantages in the fight against infectious diseases. However, the pro‐inflammatory properties of mRNA‐LNPs vaccines may hinder the induction of antigen‐specific tolerogenic immune responses. Here, it is demonstrated that stearic acid‐doped LNPs co‐loaded with nucleoside‐modified mRNA and celastrol selectively target spleen, convert their adjuvanticity and promote a tolerogenic rather than immunogenic DCs phenotype. Furthermore, the tolerogenic mRNA vaccine also invokes the generation of antigen‐specific regulatory T cells (Tregs) in the spleen and migration of the induced Tregs to the lung. In a mouse model of allergic asthma, immunization with the tolerogenic mRNA vaccine significantly alleviated symptom induction, reducing eosinophilic granulocyte accumulation and mucus secretion. In conclusion, this spleen‐targeted mRNA‐LNPs vaccine platform induces tolerogenic immune responses, offering promise for the development of therapeutics against allergic asthma and other conditions requiring immune tolerance modulation.