查找使用阿拉丁产品的科研文献

On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis

Tiantian Zuo,Jun Zhang,Jie Yang,Rui Xu,Zongwei Hu,Zhihua Wang,Huizi Deng,Qi Shen

The desmoplastic tumor microenvironment (DTME), including overexpressed stromal cells and extracellular matrix, formed the first barrier for the accumulation and penetration of nanoparticles in tumors, which compromised the therapeutic efficacy and prognosis. In some metastatic cells, overactivity of the tricarboxylic cycle could overload the electron transport chain resulting in increased mtROS production, which triggered the mitochondria-driven tumor migration and metastasis. Hence, we developed HPBC@TRP/NPs for down-regulating the mtROS-PYK2 pathway and remodeling the DTME to inhibit tumor growth and metastasis for the first time. TPP-RSV prodrugs were synthesized and targeted at mitochondria, resulting in the scavenging of mtROS, lower PYK2 expression, and activation of the mitochondria-driven apoptotic pathway. Pirfenidone fully remodeled the DTME through inhibiting the expression of CAFs, hyaluronan and collagen I, thereby reducing IFP, eliminating the immunosuppressive microenvironment by decreasing the expression of TGF-β, and increasing the infiltration of cytotoxic T lymphocytes. The combination therapy of different mechanisms via targeting the mtROS-PYK2 pathway and CAFs might provide deeper insights into the inhibition of malignant breast cancer growth and metastasis.

Fluorinated albumin nanocages dually target CAFs and tumor cells to potentiate bladder cancer chemoimmunotherapy

Zhijun Miao,Anan Xu,Gang Shen,Siyi Tang,Jie Luo,Jiajian Yang,Zhe Chen,Jinxian Pu,Tao Yang

Immunogenic cell death (ICD) induced by chemotherapeutics holds promise for cancer therapy, but limited drug penetration across the bladder mucosa and an immune-excluded tumor microenvironment (TME) have hindered success in bladder cancer. Here, we develop fluorinated albumin nanocages as transmucosal delivery vesicles that concurrently target cancer-associated fibroblasts (CAFs) and tumor cells to potentiate chemoimmunotherapy. Surface fluorination enables mucosal penetration, while recognition of secreted protein acidic and cysteine-rich (SPARC) protein ensures selective uptake by CAFs and tumor cells. Encapsulated chemotherapeutics enhance ICD through inhibition of the Bcl-2 pathway, promoting tumor cell death. Simultaneous CAF disruption reduces stromal fibrosis, facilitating anti–PD-L1 antibody delivery and T-cell infiltration. This dual-targeting strategy synergizes ICD with immune checkpoint blockade to eradicate bladder tumors by recruiting cytotoxic T cells and suppressing immunosuppressive phenotypes. Ex vivo studies in freshly resected human bladder tumors further validated the translational potential. Our findings highlight fluorinated albumin nanocages as a versatile transmucosal platform to remodel the tumor–stroma axis and amplify chemoimmunotherapy in bladder cancer.

CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling

Ai Chen,Sun Xiao,Xiao Shan,Guo Lu,Shang Mengmeng,Shi Dandan,Meng Dong,Zhao Yading,Wang Xiaoxuan,Li Jie

Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract

Thermosensitive Hydrogel Loaded with α-Mangostin for Enhanced Antitumor Effect of Doxorubicin

Tianhui Liu,Qingshuang Wang,Wenxin Geng,Xue Jiang,Changshun Lu,Zhe Zhang,Xiangru Feng

The cancer-associated fibroblasts (CAFs) in tumor stroma present substantial barriers to drug penetration, resulting in tumor resistance and progression. One promising strategy is to reprogram CAFs into a quiescent state, which necessitates novel approaches. Our study introduces a sequential treatment strategy using chitosan thermosensitive hydrogels loaded with α-Mangostin (α-M), a small molecule drug with antifibrotic properties, aimed at reprogramming CAFs within the breast cancer tumor microenvironment (TME). We developed glutathione (GSH)-responsive nanoparticles (NPc) that carry the chemotherapeutic drug doxorubicin (DOX). Treatment with α-M results in the downregulation of CAF-specific biomarkers and a remodeled TME, which improves the penetration of NPc/DOX deep into the tumor tissue. This strategy holds great promise in enhancing cancer therapeutic outcomes in tumors rich in CAFs, particularly in the case of breast cancer.

METTL3/CD98-mediated glutamate efflux in CAFs drives CD8+ T cell exhaustion and impedes neoadjuvant immunochemotherapy

Chunyu Feng,Su-Ran Li,Xiaoshuai Xu,Zihan Dang,Zihan Jiang,Erhui Jiang,Zhengjun Shang

Summary The role of neurotransmitters in suppressing anti-tumor immunity has garnered increasing attention. While glutamate has been extensively studied in neurological diseases, its potential role in regulating anti-tumor immunity, particularly in the context of neoadjuvant immunochemotherapy, remains underexplored. In this study, we find that glutamate levels are elevated in the plasma of head and neck squamous cell carcinoma (HNSCC) patients. The METTL3/m6A/CD98 axis in cancer-associated fibroblasts (CAFs) is a key driver of glutamate secretion. Glutamate induces CD8 + T cell exhaustion through SLC1A3 and impairs the formation of immune memory in secondary lymphoid structures. Additionally, glutamate promotes ferroptosis resistance in HNSCC. Notably, glutamate depletion enhances the efficacy of neoadjuvant immunochemotherapy. Our findings provide insights into how the METTL3/m6A/CD98 axis-mediated regulation of glutamate efflux may sensitize HNSCC to neoadjuvant immunochemotherapy.

CAFs Homologous Biomimetic Liposome Bearing BET Inhibitor and Pirfenidone Synergistically Promoting Antitumor Efficacy in Pancreatic Ductal Adenocarcinoma

Yin Zhang,Ranran Yu,Cheng Zhao,Jiawei Liang,Yixuan Zhang,Haochen Su,Jing Zhao,Hao Wu,Shijin Xu,Ziying Zhang,Lei Wang,Xiaoping Zou,Yun Zhu,Shu Zhang,Ying Lv

BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.

THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis

Zaoqu Liu,Yuhao Ba,Dan Shan,Xing Zhou,Anning Zuo,Yuyuan Zhang,Hui Xu,Shutong Liu,Benyu Liu,Yanan Zhao,Siyuan Weng,Ruizhi Wang,Jinhai Deng,Peng Luo,Quan Cheng,Xin Hu,Shuaixi Yang,Fubing Wang,Xinwei Han

Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.

Relaxin-encapsulated polymeric metformin nanoparticles remodel tumor immune microenvironment by reducing CAFs for efficient triple-negative breast cancer immunotherapy

Hongyan Zhang,Liying Chen,Yue Zhao,Ningchao Luo,Jingbin Shi,Shujun Xu,Lisha Ma,Menglin Wang,Mancang Gu,Chaofeng Mu,Yang Xiong

Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment, leading to the failure of triple-negative breast cancer (TNBC) immunotherapy. Therefore, depleting CAFs may enhance the effect of immunotherapy (such as PD-L1 antibody). Relaxin (RLN) has been demonstrated to significantly improve transforming growth factor-β (TGF-β) induced CAFs activation and tumor immunosuppressive microenvironment. However, the short half-life and systemic vasodilation of RLN limit its in vivo efficacy. Here, plasmid encoding relaxin (pRLN) to locally express RLN was delivered with a new positively charged polymer named polymeric metformin (PolyMet), which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before. In order to improve the stability of pRLN in vivo , this complex was further formed lipid poly-γ-glutamic acid (PGA)/PolyMet-pRLN nanoparticle (LPPR). The particle size of LPPR was 205.5 ± 2.9 nm, and the zeta potential was +55.4 ± 1.6 mV. LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1 luc /CAFs tumor spheres in vitro. In vivo , it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment, which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration. Thus, LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse, and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody (aPD-L1). Altogether, this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.

Saikosaponin D and paeoniflorin improve the HCC immune microenvironment via CLCF1/PD-L1 mediated crosstalk between CAFs and tumor cells

Zhou Kun,Yuan Wei,Zhang Fan

Radix Bupleuri-Radix Paeoniae Alba (RB-RPA) has the potential to ameliorate the immune microenvironment in hepatocellular carcinoma (HCC). The interactions between various cells influence the immune microenvironment. However, the effects of the active components (saikosaponin D (SSD) and paeoniflorin) of RB-RPA on HCC and the cell interactions within its microenvironment warrant further investigations. We established orthotopic mouse models of HCC using Hepa 1–6 cells (a hepatoma cell line) to investigate the infiltration of cancer-associated fibroblasts (CAFs). Following this, we knocked down CLCF1 in the CAFs to explore their interactions with Hepa 1–6 cells. We subsequently treated CAFs with SSD-paeoniflorin. In T-cell activation assays, we overexpressed PD-L1 in Hepa 1–6 cells and co-cultured these cells with T cells. Additionally, we treated HCC mice with SSD-paeoniflorin and induced the overexpression of CLCF1 in vivo. In mice with HCC, tumors were characterized by substantial infiltration of CAFs, which displayed elevated levels of the protein CLCF1. These CAFs play a role in suppressing the HCC immune microenvironment and elevating PD-L1 levels through the production of CLCF1. At the cellular level, SSD-paeoniflorin inhibited the growth of CAFs and the expression of CLCF1 and also suppressed the PD-L1 level in Hepa 1–6 cells through CAF-derived CLCF1. Mechanistically, CLCF1 may promote PD-L1 expression via the JAK/STAT3 signaling pathway. Furthermore, the overexpression of PD-L1 in Hepa 1–6 cells suppressed T cell proliferation and activation. In animal studies, SSD-paeoniflorin improved the HCC immune microenvironment by enhancing the interaction between CAFs and Hepa 1–6 cells through CLCF1. Collectively, SSD-paeoniflorin inhibits CLCF1 secretion in CAFs to downregulate PD-L1 expression in Hepa 1–6 cells and may reactivate the anti-tumor immune microenvironment in HCC.

Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer

Chunjing Guo,Wei Zhang,Qiaoyun Zhang,Yanguo Su,Xiaoya Hou,Qiang Chen,Huimin Guo,Ming Kong,Daquan Chen

Sequentially targeting and intervening mutual Polo-like Kinase 1 on CAFs and tumor cells by dual targeting nano-platform for cholangiocarcinoma treatment

Yue Zhou,Lei Xu,Zhangding Wang,Hongwen Liu,Xiang Zhang,Chuanjun Shu,Meng Zhang,Ting Wang,Xinyun Xu,Xiaohong Pu,Jian He,Pin Wang,Yudong Qiu,Guifang Xu,Xiaoping Zou,Yun Zhu,Lei Wang

Rationale : Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for cholangiocarcinoma (CCA) owing to the complicated crosstalk between the tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and cholangiocarcinoma cells was proposed. Methods : Genes with overexpression patterns in tumors and displaying a significant association with overall survival were identified from RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the biological roles of the key oncogene in cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo . Results : Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo . Conclusion : In summary, PLK1 is a mutual target derived from tumor cells and stroma due to its crucial role in the proliferation of tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical cholangiocarcinoma treatment.

Cancer-associated fibroblasts drive lung adenocarcinoma progression via THBS2-mediated epithelial-mesenchymal transition

Ren Yuqing,Ming Ruijie,Zuo Anning,Liu Shutong,Ba Yuhao,Zhang Yuyuan,Chen Yukang,Pan Teng,Luo Peng,Cheng Quan,Deng Jinhai,Yue Yi,Xu Hui,Weng Siyuan,Han Xinwei,Zhou Dongdong,Liu Zaoqu

The role of cancer-associated fibroblasts (CAFs) in the initiation and invasion phases of human lung adenocarcinoma (LUAD) development is not fully understood. In this study, we utilized single-cell RNA sequencing, spatial transcriptomics, and a combination of in vivo and in vitro models to decode the dynamics of tumor-stroma interactions during human LUAD progression, focusing primarily on adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). We identified a matrix CAF (mCAF) subtype characterized by high THBS2 expression, which was closely associated with poor clinical outcomes, tumor recurrence, and the invasive dynamics of LUAD. Spatial transcriptomics and multiplex immunohistochemistry analysis revealed that this CAF subpopulation was closely associated with tumor cells, with clear spatial colocalization. In vivo and in vitro experiments demonstrated that THBS2 secreted by these mCAFs directly binds to SDC4 on tumor cells, enhancing tumor epithelial-mesenchymal transition (EMT) programs. This study highlights THBS2+ mCAFs as key regulators of tumor-stroma interactions and identifies the THBS2-SDC4-EMT axis as a potential therapeutic target in LUAD.