International Journal of Biological Sciences
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2025
·Vol. 21
·期 8
·3555
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IF 10
Pengyi Liu,Minmin Shi,Yang Liu,Yihao Liu,Jiayu Lin,Shuyu Zhai,Yizhi Cao,Dongjie Chen,Yongsheng Jiang,Chenghong Peng,Lei Zhang,Chunyong Ding,Lingxi Jiang,Baiyong Shen
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. Methods: A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various in vitro and in vivo assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. Results: D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. Conclusion: D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.
研究领域:
肿瘤学
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免疫学
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药理学
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PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 4
·1309
·
IF 5.4
Yanlin Feng,Yumei Xu,Zhaoyang Wen,Xin Ning,Jianlin Wang,Deping Wang,Jimin Cao,Xin Zhou
Background: Triple-negative breast cancer (TNBC) was closely related to high metastatic risk and mortality and has not yet found a targeted receptor for targeted therapy. Cancer immunotherapy, especially photoimmunotherapy, shows promising potential in TNBC treatment because of great spatiotemporal controllability and non-trauma. However, the therapeutic effectiveness was limited by insufficient tumor antigen generation and the immunosuppressive microenvironment. Methods: We report on the design of cerium oxide (CeO2) end-deposited gold nanorods (CEG) to achieve excellent near-infrared photoimmunotherapy. CEG was synthesized through hydrolyzing of ceria precursor (cerium acetate, Ce(AC)3) on the surface of Au nanorods (NRs) for cancer therapy. The therapeutic response was first verified in murine mammary carcinoma (4T1) cells and then monitored by analysis of the anti-tumor effect in xenograft mouse models. Results: Under near-infrared (NIR) light irradiation, CEG can efficiently generate hot electrons and avoid hot-electron recombination to release heat and form reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and activating part of the immune response. Simultaneously, combining with PD-1 antibody could further enhance cytotoxic T lymphocyte infiltration. Conclusions: Compared with CBG NRs, CEG NRs showed strong photothermal and photodynamic effects to destroy tumors and activate a part of the immune response. Combining with PD-1 antibody could reverse the immunosuppressive microenvironment and thoroughly activate the immune response. This platform demonstrates the superiority of combination therapy of photoimmunotherapy and PD-1 blockade in TNBC therapy.Keywords:cerium end-deposited gold nanorods;photoimmunotherapy;PD-1 blockade;triple-negative breast cancer
研究领域:
纳米技术
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癌症治疗
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免疫学
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PubMed
高影响因子
ACS Applied Polymer Materials
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2026
·
IF 5.2
Yiwei Li,Xu Jiang,Chuntao Chen,Xiao Fu,Dongping Sun
The dense stromal barrier of pancreatic cancer (PC) severely limits chemotherapeutic efficacy. Although combination therapy is a standard clinical approach, it often exacerbates systemic toxicity. To address the dual challenges of localized drug delivery and immune activation, we developed an injectable, multifunctional hydrogel system for the synergistic codelivery of an anti-PD-1 antibody and chemotherapeutic agents (gemcitabine/albumin-bound paclitaxel). This system is based on a novel, fully natural-source composite material─methacrylated silk fibroin (SilMA) and methacrylated chitosan (CSMA). Its core innovations include: in situ gelation via a mild LAP-photoinitiation process preserves antibody bioactivity and bioactive degradation products derived from the natural polymers, which may help establish a favorable peritumoral microenvironment. In an orthotopic PC mouse model, a single peritumoral injection of this hydrogel (HLGP group) significantly enhanced tumor infiltration of CD8+ T cells, suppressed tumor growth, and outperformed all control groups, including the free-drug combination group. This study presents a unique, integrated local delivery strategy capable of simultaneously overcoming the stromal barrier, reducing systemic exposure and enhancing immunotherapy efficacy, thereby offering a promising translational pathway for the treatment of pancreatic cancer.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Jian Wu,Zhiqiang Chen,Haojie Shang,Yonghua Tong,Wen Deng,Yu He,Xiaozhuo Ba,Zichen Zhong,Yongke Bai,Tao Ye,Xiaoqi Yang,Kehua Jiang,Yijing Liu,Kun Tang
Limited lymphocyte infiltration and insufficient tumor immunogenicity remain major challenges for effective immunotherapy in bladder cancer, particularly in immunologically “cold” tumors with a highly suppressive immune microenvironment. Effective activation of the innate immune system is critical for initiating a robust adaptive anti-tumor immune response, primarily mediated by dendritic cells (DCs). Here, we designed genetically engineered hybrid membrane-coated nanoparticles (HM-MPS NPs) with excellent photothermal stability, tumor-targeting capability, and biocompatibility. HM-MPS NPs demonstrated significant tumor-suppressive effects in multiple preclinical models, including murine subcutaneous, orthotopic, and distant bladder tumor models. By combining photothermal therapy (PTT), a STING agonist (SR717), and antigen presentation, HM-MPS NPs achieve triple activation of DCs, leading to enhanced T-cell activation and a remodeled immune microenvironment. Furthermore, HM-MPS NPs synergize effectively with anti-PD-1 therapy, amplifying immunogenic cell death (ICD) and overcoming immune suppression within the tumor microenvironment. This strategy significantly boosts tumor immunogenicity and enhances anti-tumor immune responses, offering a promising approach for bladder cancer treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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高影响因子
Advanced Materials Interfaces
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2026
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IF 4.5
Chunmin Jia,Yimin Lei,Hong Xu,Xin Meng,Yuxiang Wei,Peixian Li,Xiaohua Ma,Yue Hao,Xiaohui Jia
Programmed death-1 (PD-1) is a key biomarker for monitoring therapeutic response and resistance in non-small cell lung cancer (NSCLC) immunotherapy. Achieving highly sensitive, real-time detection of PD-1 is crucial for early prediction of treatment resistance and disease recurrence. However, current methods such as ELISA suffer from limitations in sensitivity, speed, and cost. To address these challenges, we develop a label-free biosensor based on semiconducting single-walled carbon nanotube field-effect transistors (CNT-FETs). The sensing interface is designed by wrapping s-SWCNTs with poly[9-(1-octylnonyl)-9H-carbazole] (PCz), enabling immobilization of anti-PD-1 antibodies via cation-π interactions. XPS analysis confirms antibody immobilization via reversible binding energy shifts in C 1s and N 1s spectra upon salt treatment, consistent with cation-π interactions, further validated by NaCl and imidazole competition assays. Using this strategy, the sensor achieves a detection limit of 8.39 fg/mL for murine PD-1—three orders of magnitude lower than ELISA, along with good specificity and favorable regeneration capability. In human serum, it shows promising performance, with 12 out of 14 NSCLC patient samples (85.7%) exhibiting good linear correlation. With rapid response, low cost, and simple operation, this platform offers a reliable strategy for point-of-care PD-1 monitoring during NSCLC immunotherapy.
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Journal for ImmunoTherapy of Cancer
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2025
·Vol. 13
·期 6
·e012144
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IF 10.6
Shiru Chen,Yuchong Zhao,Mengdie Cao,Wang Peng,Hai Huang,Yilei Yang,Jingwen Liang,Wei Chen,Shuya Bai,Qiaodan Zhou,Jiamei Jiang,Yilin Gu,Ronghua Wang,Bin Cheng
Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic and immunosuppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint inhibitors such as anti-programmed cell death 1 (PD-1). Methods This study aimed to evaluate the therapeutic potential of Y126S, a recombinant IgG1/IgG2 hybrid bispecific antibody (BsAb), in reshaping the immunotherapy-resistant TME in PDAC. Orthotopic PDAC and KPC (Kras LSL-G12D/+ ; Trp53 LSL-R172H/+ ; Pdx1-Cre) mouse models were established and treated with Y126S, α-connective tissue growth factor (CTGF), α-PD-1, or a combination of α-CTGF and α-PD-1. TME remodeling, antibody distribution, and therapeutic efficacy were assessed using flow cytometry, immunohistochemical/Masson staining, atomic force microscopy, positron emission tomography (PET) imaging, distribution analysis, and other experimental techniques. Results Here, Y126S was characterized in vitro and its antitumor efficacy was evaluated and validated in orthotopic PDAC mice and KPC mouse models. Notably, Y126S significantly remodeled the TME and demonstrated superior tumor-specific accumulation compared with single α-PD-1 treatment, leading to markedly enhanced antitumor efficacy relative to its parental antibodies or their combination. Mechanistically, Y126S suppressed cancer-associated fibroblasts (CAFs) activation, reduced collagen deposition, and downregulated programmed cell death ligand 1 (PD-L1) expression on CAFs by targeting CTGF and enhanced the anti-PD-1-mediated reinvigoration of cytotoxic CD8 + T cells, thereby establishing a less desmoplastic and potent tumor-killing microenvironment. Conclusions Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME.
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PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Chun Wang,Yuanhao Jing,Wenting Yu,Jie Gu,Zijian Wei,Anni Chen,Ying-Tzu Yen,Xiaowen He,Lanqi Cen,Aoxing Chen,Xueru Song,Yirong Wu,Lixia Yu,Gaojian Tao,Baorui Liu,Shoufeng Wang,Bin Xue,Rutian Li
Doxorubicin (DOX) is the classic soft tissue sarcomas (STS) first-line treatment drug, while dose-dependent myelosuppression and cardiotoxicity limit its application in clinic. This research intends to apply DOX, which is also an inducer of immunogenic cell death as a part for “in situ vaccination” and conjointly uses PD-1 inhibitors to enhance antitumor efficacy. In order to achieve the sustained vaccination effect and real-time monitoring of distribution in vivo, the in situ forming and injectable hydrogel platform with the function of visualization is established for local delivery. The hydrogel platform is synthesized by hyaluronic acid-dopamine coordinated with gadolinium ions (Gd 2+ ). Gd 2+ provides the ability of magnetic resonance imaging, meanwhile further cross-linking the hydrogel network. Experiments show excellent ability of sustained release and imaging tracking for the hydrogel platform. In mouse STS models, the “in situ vaccination” hydrogels show the best effect of inhibiting tumor growth. Further analysis of tumor tissues show that “in situ vaccination” group can increase T cell infiltration, promote M1-type macrophage polarization and block elevated PD-1/PD-L1 pathway caused by DOX. These results are expected to prove the potential for synthesized hydrogels to achieve a universal platform for “in situ vaccination” strategies on STS treatments.
研究领域:
癌症研究
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药学
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生物医学工程
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免疫治疗
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医学成像
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PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-10
·
IF 3.9
Mo Fei,Hong Min,Chen Xiao,Wang Qiye,Dong Chao
The accumulation of regulatory T cells (Tregs) in the tumor microenvironment is a key factor for immunosuppression and immune escape of cancer cells. Genistein is a natural isoflavonoid in soybeans, possessing a wide range of pharmacological bioactivities. However, the immunomodulatory potential of genistein remains largely unexplored. This study investigated the synergistic efficacy of genistein with anti-PD-1 therapy in a mouse model of melanoma. The regulatory role of genistein in Treg differentiation and functional stability was also examined in this study. The antitumor effects of genistein, alone or in combination with anti-PD-1 therapy, were evaluated in the mouse B16-F10 melanoma model. The profiles of intratumoral Tregs and CD8 + cytotoxic T cells were profiled using flow cytometry. The impact of genistein on the suppressive function and differentiation of Tregs was also studied in vitro. RT-qPCR, Western blotting and flow cytometry were conducted to characterize the functional phenotype of Tregs under genistein treatment. Genistein showed a synergistic effect with anti-PD-1 therapy in B16-F10 melanoma models, achieving enhanced immune infiltration and functional reprogramming of the tumor microenvironment. This combinatorial strategy not only reduced intratumoral Tregs but also elevated the CD8 + /Treg ratio. At the mechanistic level, genistein effectively suppressed critical Treg surface markers, which are indispensable for Treg-mediated immunosuppression. Furthermore, it disrupted Treg differentiation by attenuating PI3K/AKT signaling phosphorylation. Our data demonstrated that genistein boosts the antitumor effect of anti-PD-1 therapy by impairing the immunosuppressive function and differentiation of Tregs, indicating that genistein has the potential to enhance the treatment outcome of the immune checkpoint inhibitor.
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高影响因子
Theranostics
·
2026
·Vol. 16
·期 7
·3408
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IF 13.3
Binbin Ji,Hui Guo,Rong Xing,Miaomiao Sun,Yu Cheng,Chen Yao,Hanyong Zhu,Xuerong Wang,Ruihan Jiang,Xin Chen,Zimeng Liu,Suyan Wang,Fei Xu,Fangyu Zhang,Fuxing Dong,Xiucheng Pan,Jing Yang,Yuchen Pan
Rationale: Macrophage phagocytosis is essential for pathogen clearance during sepsis. We previously demonstrated that the glycolytic enzyme 6-phosphofructokinase, muscle type (PFKM), modulates macrophage functions and its deficiency alleviates sepsis in mice. However, the function of PFKM in regulating macrophage phagocytosis remains unclear. Methods: CD14 + monocytes were sorted by flow cytometry from healthy volunteers and septic patients, and the subcellular localization of PFKM was assessed by immunofluorescence. Nuclear translocation mechanisms and PFKM-p53 interaction were identified by Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) and validated by Co-IP. Transcriptomic sequencing was used to identify the downstream target of the PFKM-p53 complex. Inflammatory cytokine levels were detected by ELISA and real-time RT-PCR, and the phagocytosis of macrophages was assessed by flow cytometry. Dual-luciferase reporter assays and ChIP were employed to investigate whether PFKM acts as a co-regulator of p53 in mediating Pdcd1 transcription. Nanobodies targeting PFKM-p53 were screened and subsequently synthesized according to the sequences. The effect of nuclear PFKM and the therapeutic effect of nanobodies were evaluated on the well-established sepsis mouse models induced by Escherichia coli or cecal ligation and puncture. Results: PFKM translocated to the macrophage nucleus during sepsis. Nuclear accumulation of PFKM impaired phagocytosis through a non-glycolytic “moonlighting” function and exacerbated sepsis. Mechanistically, PFKM interacts with p53, which facilitates its nuclear translocation. Subsequently, PFKM promotes p53 acetylation at K120, enhancing p53 binding to the Pdcd1 promoter and driving its transcription, thereby suppressing macrophage phagocytosis. Blocking the PFKM-p53 interaction with a nanobody, Nb07, restored phagocytosis of macrophages and alleviated sepsis in mice. Conclusion: Our data reveal the PFKM-p53-PD-1 axis that suppresses macrophage phagocytosis in sepsis and highlight the therapeutic potential of targeting this pathway with nanobody-based strategies.
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高影响因子
Theranostics
·
2026
·Vol. 16
·期 13
·7571
·
IF 14.9
Linlin Song,Meixu Chen,Huiling Wang,Xin Wang,Tianyue Xu,Heqing Zhang,Shuwen Ran,Liwen Huang,Yingying Ma,Zhihui Liu,Zihan Xu,Yujie Zhao,Zichang Liu,Yong Luo,Xiujun Yu,Yulan Peng,Hubing Shi,Jing Jing,Xiujing He
Rationale Triple-negative breast cancer (TNBC) remains one of the most aggressive subtypes due to its poor immunogenicity and resistance to systemic therapies. Methods Here, we report a multifunctional NIR-II light-triggered theranostic nanoplatform, termed LQPO, that integrates liposome, Ti 3 C 2 quantum dots (QDs), perfluorohexane (PFH), and ozone to enable multimodal imaging-guided photo-gas synergistic therapy. The QDs, embedded within the liposomal bilayer, act as highly efficient NIR-II photothermal transducers, while the PFH core serves as a liquid-gas phase-change medium capable of dissolving and releasing ozone under localized heating. Results Upon NIR-II irradiation, LQPO produced strong photothermal and photoacoustic signals for real-time photoacoustic (PA) and contrast-enhanced ultrasound (CEUS) imaging, accompanied by vaporization of the PFH core and burst release of ozone. This spatiotemporally coordinated cascade induced potent oxidative stress and hyperthermia, synergistically driving GSDME-dependent pyroptosis and immunogenic cell death (ICD). The resulting “in situ vaccination” effect remodeled the tumor immune microenvironment and primed tumors for PD-1 blockade therapy. In vivo , NIR-II-activated LQPO achieved efficient tumor accumulation, strong PA/CEUS imaging contrast, and pronounced inhibition of both primary and abscopal tumors when combined with αPD-1 therapy. No significant systemic toxicity was observed, confirming its favorable biosafety. Conclusions Overall, this study establishes a single-laser-activated nanoplatform that unifies real-time multimodal imaging and photo-gas synergistic therapy, and converts localized treatment into a systemic antitumor immune response upon integration with checkpoint inhibition.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Hongyu Yang,Yuelin Zhao,Sen Mu,Siqi Wang,Aiyang Tong,Dongkai Wang,Jiajia Jia,Ji Li
HA@CZ enables acid-responsive local Ca 2+ /Zn 2+ ion therapy. • Zn 2+ impairs Ca 2+ extrusion and drives sustained Ca 2+ overload. • Dual-ion stress induces caspase-1/GSDMD and caspase-3/GSDME pyroptosis. • HA@CZ cascade-induces pyroptosis and activates the STING pathway. • Local HA@CZ treatment sensitizes 4 T1 tumors to PD-1 blockade. Triple-negative breast cancer responds poorly to immune checkpoint blockade, partly because of insufficient tumor-local immune priming. Controlled delivery of bioactive ions offers an opportunity to induce inflammatory tumor cell death while limiting nonspecific systemic exposure. Here, we developed hyaluronic acid-modified, zinc containing calcium carbonate nanoparticles (HA@CZ) for acid-responsive synchronized Ca 2+ /Zn 2+ delivery. HA@CZ remained colloidally stable under physiological conditions but released Ca 2+ and Zn 2+ more rapidly under tumor relevant acidic conditions. HA@CZ markedly promoted intracellular Ca 2+ /Zn 2+ accumulation, induced mitochondrial dysfunction, and triggered gasdermin dependent pyroptosis through the caspase-1/GSDMD and caspase-3/GSDME axes. Mechanistically, the key distinction of HA@CZ does not lie in Ca 2+ overload alone, but in converting Ca 2+ overload from a direct ion burden process into a Zn 2+ initiated Ca 2+ homeostasis collapse mechanism. Zn 2+ impaired mitochondrial energy metabolism and ATP dependent Ca 2+ extrusion, thereby lowering the threshold for sustained Ca 2+ overload after synchronized ion release. The resulting dual ion stress promoted mitochondrial deoxyribonucleic acid leakage and activated cyclic GMP–AMP synthase stimulator of interferon genes signaling, thereby coupling tumor cell pyroptosis with endogenous deoxyribonucleic acid sensing activation. In syngeneic 4 T1 tumor models, HA@CZ suppressed tumor growth after both systemic and local administration, promoted dendritic cell maturation and CD8 + T-cell infiltration, and remodeled the tumor immune microenvironment toward a pro-inflammatory phenotype. Intratumoral studies confirmed its intrinsic therapeutic superiority over free CaCO₃, Zn 2+ , and their physical mixture, while combination with anti-PD-1 therapy enhanced control of both primary and distant tumors. Furthermore, tumor re-challenge experiments demonstrated that HA@CZ induced durable antitumor immune memory. These findings establish HA@CZ as a controlled-release ion nanotherapeutic that couples synchronized Ca 2+ and Zn 2+ delivery to pyroptosis associated immune activation and checkpoint blockade sensitization. Download: Download high-res image (150KB) Download: Download full-size image
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Yingying Zhao,Beibei Zhang,Shaobo Duan,Yaqiong Li,Yuzhou Wang,Yongchao Wang,Juan Zhang,Rong Huang,Ru Jiang,Rui Zhang,Qi Zhou,Linlin Zhang,Xiaoxia Xu,Zesheng Li,Si Chen,Lianfeng Mo,Xu Zhang,Siyi Yang,Xiguo Cai,Lianzhong Zhang
Metabolic competition and accumulation of metabolic byproducts in the tumor microenvironment (TME) severely impair the antitumor functions of T cells, leading to suboptimal outcomes in cancer immunotherapy. To address these challenges, we developed an ultrasound-visualized methionine partitioning nano-modulator utilizing erythrocyte membrane-hybridized liposomes loaded with the glycolysis inhibitor lonidamine (LND) and small interfering RNA (siRNA) against methionine transporter solute carrier family 43, member 2 (SLC43A2). By downregulating SLC43A2 expression to reduce methionine uptake by tumor cells and suppressing tumor glycolysis to alleviate the acidic TME, the nano-modulator enhances methionine availability for T cells and improves T cell activity. Moreover, the oxygen-enriched perfluorohexane (PFH-O 2 ) loaded in the core of the nano-modulator alleviates tumor hypoxic, further reducing the glycolysis rate of tumor cells. Furthermore, ultrasound-triggered liquid-gas phase transitions enable real-time ultrasound contrast imaging for precise tumor visualization, while leveraging the ultrasonic cavitation effect to enhance drug penetration and release at the tumor site. In summary, this ultrasound-visualized methionine partitioning nano-modulator effectively reshapes tumor metabolism and immunosuppressive TME under ultrasound guidance, thereby significantly improving the efficacy of tumor immunotherapy. These findings demonstrate a promising strategy for enhancing immunotherapy outcomes through metabolic modulation and microenvironment regulation.
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