Asian Journal of Pharmaceutical Sciences
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2025
·
IF 11.9
Wei-Ran Cao,Xue Zhang,Jia-Xuan Chen,Lu Sun,Hui-Ning He,Fei Yu
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. In vivo , strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
研究领域:
肿瘤学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BMC CANCER
·
2025
·Vol. 25
·期 1
·1-10
·
IF 3.4
Liu Shiyuan,Guan Tian,Yang Futian,Zhang Honglei,Yao Yao,Huang Jiman,Zhao Pengfei,Huang Wei,Wu Tailiang,Lin Hui,Fu Ting,Chen Shaoyu,Dai Pengzhan,Ding Zhechun,Chen Dongmei,Li Wei,Zeng Haoyu,Zhang Xianjun
Human oral tongue squamous cell carcinoma (OTSCC) is a prevalent form of head and neck squamous cell carcinoma (HNSCC), often presenting at an advanced stage with a grim prognosis. Traditional therapeutic approaches such as surgery, adjuvant radiotherapy, and chemoradiotherapy have shown limited efficacy in treating advanced OTSCC, underscoring the urgent need for innovative treatment strategies. Our bioinformatics analysis identified CD276 as a significant biomarker in OTSCC, with high protein expression levels correlating to a markedly reduced survival rate in late-stage patients. This discovery has led us to develop chimeric antigen receptor-natural killer (CAR-NK) cells derived from umbilical cord blood cells (UCBCs), specifically targeting CD276. Our aim is to investigate this novel therapeutic approach for its potential to combat OTSCC under pre-clinical conditions. Our in vitro and ex vivo studies have demonstrated that CD276-targeted CAR-NK cells exhibit remarkable efficacy in lysing OTSCC cell lines and primary cells, as well as in eliminating OTSCC organoids. These promising results underscore the pivotal role of CD276 in OTSCC pathogenesis and highlight the potential of CAR-NK cell therapy as a groundbreaking treatment option for advanced-stage OTSCC, offering new hope for translational medicine in the field of stomatology.
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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DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2024
·Vol. 12
·期 5
·e008662
·
IF 10.3
Gan Xiong,Zhi Chen,Qianwen Liu,Fang Peng,Caihua Zhang,Maosheng Cheng,Rongsong Ling,Shuang Chen,Yu Liang,Demeng Chen,Qimin Zhou
Background CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic. Methods We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276 wKO ) and K14cre; CD276 conditional knockout (CD276 cKO ) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion. Results In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs’ formation and reducing NK cells in vivo. Conclusions This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.
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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癌症生物学
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DOI
PubMed
高影响因子
Communications Biology
·
2026
·
IF 5.8
Liu Lu,Wang Zhuolin,Xiang Qin,Rong Huan,Xie Chunyang,Tian Rui,Zheng Zeze,Xu Ruqing,Mei Ligang,Song Jiong,Lin Changhai,Yang Feng,Huang Xue,Xiang Tingxiu,Yang Aimin
Protein S -palmitoylation is catalyzed by a family of zinc finger Asp-His-His-Cys (ZDHHC) domain-containing palmitoyl acyltransferases, most of which are widely expressed in normal tissues and aberrantly increased in diverse malignant tumor tissues. However, the mechanisms of action of S -palmitoylation in tumor development are not fully understood. Here we profile interacting proteins of ZDHHC4, a member of the ZDHHC family, and further characterize the immune checkpoint CD276 as a substrate of ZDHHC4. ZDHHC4 mediates S -palmitoylation of CD276 at Cys488 and Cys496, which is reversed by palmitoyl-protein thioesterases (PPT1/2). Consequently, S -palmitoylation enhances the plasma membrane targeting of CD276 and increases its protein stability. Moreover, S -palmitoylation of CD276 promotes breast cancer cell proliferation and migration, and contributes to tumor growth in murine xenograft models. Thus, our study reveals an important molecular mechanism of S -palmitoylation in the regulation of CD276 function, highlighting the therapeutic potential of targeting ZDHHC4-CD276 signaling axis in breast cancer.
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DOI
高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Xiaojuan Huang,Leina Ma,Yangyang Lu,Jinfeng Cui,Weiwei Qi,Jialin Song,Jing Guo,Shasha Wang,Jing Fang,Zhimin Lu,Wensheng Qiu
The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demonstrate that CD276, an immune checkpoint protein, promotes TKI resistance in HCC by reprogramming lipid metabolism. Upon TKI treatment, CD276 binds pSTAT3 and undergoes importin α/β-dependent nuclear translocation. In the nucleus, CD276 cooperates with STAT3 to promote CD36 transcription, thereby potentiating fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation. This metabolic rewiring drives HCC proliferation and confers TKI resistance. Importantly, pharmacological inhibition of CD36 with sulfosuccinimidyl oleate sodium suppresses fatty acid uptake and tumor lipid metabolism, resensitizing resistant HCC cells to TKIs. Our findings reveal the CD276-STAT3-CD36 axis as a key regulator of lipid metabolic reprogramming in TKI resistance, providing a promising therapeutic target to overcome treatment resistance in HCC.
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PubMed
高影响因子
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