Journal of Advanced Research
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2025
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IF 13
Xueni Sun,Jing Xia,Haiyang Jiang,Ting Duan,Chunli Zhang,Qinyi Li,Zuyi Yang,Ruonan Zhang,Xia Ding,Xidong Gu,Xiaohong Xie,Tian Xie,Xinbing Sui
Introduction Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer associated with a poor prognosis. A better understanding of IBC’s pathological and molecular basis is crucial for developing precision medicine strategies. Objective This study aimed to profile IBC at both the single-cell and spatial levels to examine immune cell populations, signaling pathways, and identify potential therapeutic targets for treating IBC. Methods Single-cell RNA sequencing (scRNA-seq) was employed to identify immune-related differences between IBC and non-IBC samples. qRT-PCR and fluorescence staining were utilized to validate the findings from scRNA-seq, while spatial analysis using the NanoString GeoMx Digital Spatial Profiler was conducted to evaluate immune cell infiltration. Tumor-immune cell co-culture assays were conducted to assess the cytotoxic role of CXCL13. In vivo studies were performed to assess the effect of CXCL13 on the efficacy of immunotherapy. Furthermore, a screening of natural products was performed to identify potential immunomodulatory agents for the treatment of IBC. Results scRNA-seq revealed a significant reduction in CXCL13 expression in T cells within the IBC tumor microenvironment, a finding that correlated with poorer patient outcomes. Additionally, immune-related gene sets were notably downregulated, and cell–cell interactions were diminished, indicating a state of immune suppression within IBC. Spatial analysis further demonstrated a reduced presence of CD45-positive immune cells within IBC tumor tissues, highlighting the compromised immune infiltration characteristic of this aggressive cancer subtype. Most importantly, overexpression of CXCL13 in tumor cells, under co-culture with immune cells, significantly promoted tumor cell death. CXCL13 can also enhance the efficacy of anti-PD-1 therapy in vivo . Furthermore, screening of natural products identified sanguinarine and α-mangostin as potential immunomodulatory compounds, offering promising therapeutic avenues for modulating the immune response in IBC and improving treatment outcomes. Conclusion Our findings reveal inherent heterogeneity within the “cold” tumor microenvironment of IBC. These factors collectively contribute to the immune suppression characteristic of IBC. Additionally, natural product screening identified sanguinarine and α-mangostin as promising immunomodulatory agents, offering potential therapeutic strategies to improve treatment outcomes.
研究领域:
肿瘤学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
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2024
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IF 4.8
Ruoyun Dong,Li Li,Hongmei Chang,Guanling Song,Sixiu Liu
Titanium dioxide nanoparticles (TiO 2 NPs) can reduce sperm number, but the mechanisms of defective spermatogenesis induced by TiO 2 NPs have not been studied through cell-cell interactions at present. A kind of biomimetic three-dimensional blood−testis barrier microfluidic chip capable of intercellular communication was constructed with soft lithography techniques, including Sertoli cell (TM4), spermatogonia (GC-1) and vascular endothelial cell units, to study the mechanisms of TiO 2 NPs-induced defective spermatogenesis. TM4 and GC-1 cells cultured in TiO 2 NPs exposure and control chips were collected for transcriptomics and metabonomics analysis, and key proteins and metabolites in changed biological processes were validated. In TM4 cells, TiO 2 NPs suppressed glucose metabolism, especially lactate production, which reduced energy substrate supply for spermatogenesis. TiO 2 NPs also decreased the levels of key proteins and metabolites of lactate production. In GC-1 cells, TiO 2 NPs disturbed chemokine signaling pathways regulating cell proliferation and interfered with glutathione metabolism. The Cxcl13, Stat3 and p-Stat3 levels and cell proliferation rate were decreased, and the GSR, GPX4 and GSH contents were increased in GC-1 cells in chips under TiO 2 NPs treatment. The decrease in energy substrate supply for spermatogenesis and inhibition of spermatogonia proliferation could be the main mechanisms of defective spermatogenesis induced by TiO 2 NPs.
研究领域:
纳米技术
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生殖生物学
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细胞生物学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2024
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IF 27.4
Qingshuang Zou,Ke Liao,Guangchao Li,Xin Huang,Yongwei Zheng,Gun Yang,Min Luo,Evelyn Y. Xue,Chuanqing Lan,Shuai Wang,Yao Shen,Dixian Luo,Dennis K. P. Ng,Quan Liu
The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can “warm” the “cold” tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr 3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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生物医学工程
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）