Gongbo Fu

Kcnn4 (KCa3.1) is a calcium‐activated potassium channel involved in cell volume regulation and immune cell function, but its role in salivary gland homeostasis remains poorly understood. In this study, we generated constitutive Kcnn4 knockout ( Kcnn 4 ^−/− ) mice to investigate the impact of Kcnn4 loss on salivary glands and systemic inflammation. Histological examination revealed that Kcnn 4 ^−/− mice had enlarged salivary glands with increased collagen deposition (fibrosis) but no major disorganization on H&E staining. mRNA‐seq identified 473 differentially expressed genes (DEGs), with significant enrichment of T‐ and B‐cell‐related pathways. Immunofluorescence showed markedly increased infiltration of CD4 ⁺ , CD8 ⁺ T cells and CD19 ⁺ B cells into the salivary glands of knockout mice, yet local IgG levels were significantly decreased, which was confirmed by western blotting. Olink proteomic analysis of serum from Kcnn 4 ^−/− mice revealed that among 43 targeted inflammatory proteins, 16 were significantly changed; 15 of these (including Il‐6, Tnf, Cxcl1) were decreased, while only Csf1 was increased, indicating a broad systemic anti‐inflammatory shift. Collectively, these findings demonstrate that Kcnn4 deficiency induces salivary gland fibrosis, promotes T/B cell infiltration, impairs local antibody production, and suppresses systemic inflammatory mediators, uncovering an unexpected role of Kcnn4 in integrating tissue remodeling and immune function in the salivary gland.

Orthotopic liver transplantation (OLT) remains the gold standard treatment for end-stage liver disease but is severely limited by donor scarcity and immune rejection. Consequently, bioartificial liver (BAL) systems and hepatocyte transplantation have emerged as promising alternatives, yet their clinical efficacy hinges on the unresolved challenge of generating functional hepatocytes at scale. This review systematically examines the molecular landscape governing hepatocyte proliferation, dissecting the key regulatory roles of Wnt/β-catenin, Hippo-YAP, Notch, and TGF-β signaling pathways in balancing proliferation and differentiation. We critically evaluate current in vitro expansion strategies, contrasting viral-mediated genetic modification approaches with emerging non-genome-editing strategies. Particular emphasis is placed on "next-generation" methodologies, including chemically defined media, bioreactor-based dynamic cultures, and multicellular co-culture systems that recapitulate the native hepatic niche. Furthermore, we highlight recent breakthroughs in liver organoid technology-such as the construction of multi-zonal and vascularized architectures-that bridge the gap between in vitro expansion and in vivo physiological relevance. Finally, we summarize the translational progress of these expanded hepatocytes in BAL devices, cell transplantation trials, and high-fidelity pharmacotoxicological models. We further discuss how emerging technologies, including CRISPR-Cas9-mediated gene correction and bioengineering innovations, may help address current limitations, while acknowledging that substantial preclinical validation remains necessary.

Non-genetically modified adoptive cell therapies (ACTs) represent a rapidly advancing frontier in solid tumor immunotherapy, offering a safe and adaptable alternative to genetically engineered approaches by capitalizing on the intrinsic plasticity of immune cells. Genetic engineering strategies, including CAR-T cells, encounter significant obstacles in solid tumors, including on-target off-tumor toxicity, an immunosuppressive tumor microenvironment, and drug resistance. Although non-genetically modified ACTs-including tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer (NK) cells, and γδ T cells-offer unique advantages, their clinical application remains underexplored. This review consolidates the mechanistic basis, clinical progress, and limitations of non-genetically modified ACTs, proposing a paradigm shift toward combinatorial strategies. We systematically assessed how TILs overcome tumor microenvironment (TME) inhibition through lymphodepletion and cytokine assistance, compared the histocompatibility complex-unrestricted cytotoxicity of CIK cells with their functional diversity, and emphasized the innate flexibility of NK/γδ T cells against antigen-loss variants. By integrating preclinical and clinical data, we identify critical challenges: in vitro expansion inefficiency, absence of standardized protocols, and dynamic TME interactions. Furthermore, we advocated patient stratification by biomarkers, the addition of optimized cytokines, and rational combinations with checkpoint inhibitors or metabolic modulators to enhance efficacy. This review outlines the current landscape and proposes actionable solutions to reconcile the disparity between experimental potential and clinical applicability in non-genetically modified ACT.

Recent advancements in technology have significantly expanded the scope of tumor research, progressing from the study of individual cells to more intricate tissue and organ-level analyses. Tumor organoids have emerged as a highly realistic platform for investigating tumor growth, development, and their interactions with the surrounding microenvironment. However, a notable limitation of these organoids is their lack of the diverse cellular composition typically observed in actual tumors, which hinders their ability to fully replicate the complexity of the tumor microenvironment. Immune cells play a pivotal role, and tumor immunology has become a major research hotspot. Research in tumor immunology aims to elucidate how the immune system recognizes and attacks tumor cells, as well as how tumor cells evade immune surveillance. In recent years, there has been growing interest in co-culturing immune cells with tumor organoids, an approach that has yielded valuable insights into the intricate interactions between tumors and the immune system. The aim of this paper is to review and discuss the progress achieved in co-culturing tumor organoids with immune cells. By doing so, we hope to offer a new perspective and enhance our understanding of the complexity and diversity inherent in the tumor microenvironment.

Immunotherapy utilizing dendritic cells (DCs) and cytokine-induced killer (CIK) cells is a promising treatment approach for solid tumors. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of DC-CIK immunotherapy by assessing overall survival, progression-free survival, overall response rate, disease control rate, and adverse events in relevant randomized controlled trials. The results of this analysis will contribute to optimizing treatment strategies and improving cancer immunotherapy outcomes. This systematic review and meta-analysis adhered to PRISMA guidelines. A comprehensive search was conducted on multiple databases for RCTs studying the combination of DC-CIK immunotherapy for solid tumors. Inclusion criteria were RCTs comparing DC-CIK immunotherapy with control therapy and reporting OS, PFS, ORR, or DCR. Two authors independently performed study selection and data extraction, with disagreements resolved through consensus or consultation with a third reviewer. Extracted data included study characteristics, participant information, interventions, outcomes, and quality assessment. Statistical analysis was performed using Review Manager and Stata software. Heterogeneity was assessed using chi-square and I-squared statistics. Sensitivity analysis and assessment of publication bias were planned. A total of 1013 records were initially retrieved, and after a thorough screening process, 13 randomized controlled trials (RCTs) were included in the meta-analysis. These studies involved a total of 1443 patients, with 730 receiving DC-CIK immunotherapy and 713 in the control groups. The included studies covered various cancer types, with the majority conducted in mainland China. The meta-analysis showed that DC-CIK immunotherapy was associated with improved overall survival (OS) and progression-free survival (PFS) compared to control therapy. Furthermore, DC-CIK immunotherapy demonstrated higher overall response rate (ORR) and disease control rate (DCR) compared to non-DC-CIK therapy. Adverse events were reported in both groups, with fever being more common in the DC-CIK immunotherapy group and bone marrow suppression and gastrointestinal reactions more common in the control group. Sensitivity analyses confirmed the stability of the results, while publication bias was observed for PFS and fever. DC-CIK immunotherapy shows promising efficacy and safety for solid tumors, improving survival rates and response rates. Further research is needed to optimize treatment regimens and identify predictive factors.

Background: Surgical excision is considered one of the most effective treatments for secondary osteosarcoma (SO). It remains unclear whether the survival of patients with secondary osteosarcoma (SO) could be associated with their surgical willingness. Materials and methods: The statistics of the patients diagnosed with SO between 1975 and 2008 were gathered from the surveillance epidemiology and end results (SEER) database. The patients were divided into three subgroups according to their surgical compliance. The authors used the multivariable Logistic regression analysis and cox regression method to reveal the influence of surgical compliance on prognosis and the risk factors of surgical compliance. Additionally, the authors formulated a nomogram model to predict the overall survival (OS) of patients. The concordance index (C-index) was used to evaluate the accuracy and practicability of the above prediction model. Results: Sixty-three (9.2%) of the 688 patients with SO who were recommended for surgical treatment refused to undergo surgery. Lower surgical compliance can be ascribed to an earlier time of diagnosis and refusal of chemotherapy. The lower overall survival (OS) {[hazard ratio (HR)] 1.733, [CI] 1.205-2.494, P value [P]=0.003} of not surgical compliant patients was verified by the multivariate cox regression method, compared with surgical compliant patients. In addition, the discernibility of the nomogram model was proven to be relatively high (C-index=0.748), by which we can calibrate 3-year- and 5-year OS prediction plots to obtain good concordance to the actual situation. Conclusions: Surgical compliance was proved to be an independent prognostic factor in the survival of patients with SO.

Background: Cholangiocarcinoma (CCA) stands as an aggressive malignancy of the biliary tract. The interplay between the tumor and immune system plays a pivotal role in disease progression and treatment outcomes. Hence, the present study aimed to extensively explore the immunogenomic landscape of CCA, with the objective of unveiling unique molecular and immunological signatures that could guide personalized therapeutic approaches.Methods: The study collected data from The Cancer Genome Atlas databases, performed gene set variation analysis for the chemokine ligand 5 (CCL5) high/low expression group, conducted principal component analysis, gene set enrichment analysis enrichment and mutation pattern analysis, generated a heatmap, and performed cox regression analysis.Results: The two discrete subpopulations were found to exhibit contrasting mutational and immunogenomic characteristics, emphasizing the heterogeneity of CCA. These subsets also showed pronounced discrepancies in the infiltration of immune cells, indicating diverse interactions with the tumor immune microenvironment. Furthermore, the dissimilarities in mutational patterns were observed within the two CCA subgroups, with PBRM1 and BAP1 emerging as the most frequently mutated genes. In addition, a prognostic framework was formulated and validated utilizing the expression profiles of COX16 and RSAD2 genes, effectively segregating patients into high‐risk and low‐risk cohorts. Furthermore, the connections between immune‐related parameters and these risk groups were identified, underscoring the potential significance of the immune microenvironment in patient prognosis. In vitro experiments have shown that COX16 promotes the proliferation and metastasis of CCA cells, whereas RSAD2 inhibits it.Conclusions: The present study provides an intricate depiction of the immunogenomic landscape of CCA based on CCL5 expression, thereby paving the way for novel immunotherapy strategies and prognostic assessment.