NATURE IMMUNOLOGY
·
2024
·
IF 27.7
Xia Yun,Li Xin,Bie Nana,Pan Wen,Miao Ya-Ru,Yang Mei,Gao Yan,Chen Chuang,Liu Hanqing,Gan Lu,Guo An-Yuan
Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8 + T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.
研究领域:
肿瘤学
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免疫治疗
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Junhong Li,Wenxing Lv,Ziwei Han,Yike Li,Jinqi Deng,Yanjuan Huang,Shuo Wan,Jiashu Sun,Bo Dai
Chemo-immunotherapy, combining systemic chemotherapeutic drugs and immune checkpoint blockers, is a promising paradigm in cancer treatment. However, challenges such as limited induction of immune responses and systemic immune toxicity have hindered its clinical applications. Here, a zeolite imidazolate framework-8 (ZIF-8) that encapsulates mitoxantrone (MIT), an immune cell death (ICD)-inducing chemotherapeutic agent (MIT@ZIF-8), is synthesized using a one-pot aqueous-phase process. ZIF-8 serves as a dual-functional nanomaterial for chemo-immunotherapy: a carrier to enhance tumor uptake of MIT for improved chemotherapy efficacy, and a pyroptosis inducer to amplify MIT-induced ICD for augmented anti-tumor immune responses. As a result, in vivo administration of MIT@ZIF-8 markedly inhibits tumor growth in both immunologically “hot” colon cancer and immunologically “cold” prostate cancer. Moreover, MIT@ZIF-8 treatment increases the abundance of cytotoxic CD8 + T cells and reduces the amount of immunosuppressive regulatory T cells in tumors, thereby enhancing anti-tumor immunity and sensitizing prostate cancer to anti-CTLA-4 immunotherapy. In summary, MIT@ZIF-8 offers a highly translational approach for chemo-immunotherapy.
研究领域:
肿瘤学
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纳米医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2025
·
IF 6
Xin Zhang,Li Li,Haiqing Niu,Zixin Liang,Liuqi Sang,Ning Wang,Fengli Huang,Xingzhi Han,Zhihao Liu,Xiao Shi,Qun Zhang,Jing Hu,Xiaoping Qian
Background The prognosis of patients with colorectal liver metastasis (CRLM) is poor. The 5-year survival rate of those who cannot be treated by surgery is less than 5 %, thus, the management of patients with CRLM remains a significant challenge. Based on the anti-tumor activity of traditional Chinese medicine monomer and the local immune activation caused by low dose radiotherapy combined with immune checkpoint inhibitors, we jointly applied it to explore the tumor inhibitory effect and the change of local immune microenvironment in liver metastasis model. Methods We engineered biomimetic nanoparticles through macrophage membrane encapsulation of gambogic acid (GA)-loaded PLGA cores, employing a double emulsion-solvent evaporation method to fabricate M-PLGA@GA nanoparticles. In tumor-bearing mice with surgically induced colorectal liver metastasis via hemisplenectomy, therapeutic efficacy was evaluated through intratumoral administration of M-PLGA@GA combined with triple-modality therapy: low-dose radiotherapy (LDRT; 5 Gy), anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb; 200 μg), and nanoparticle delivery. This combinatorial approach leveraged spatial-temporal control of tumor microenvironment modulation. Results The nanoparticles augmented the targeted delivery ability of drugs to tumor cells and in vivo circulation duration, coupled with improved aqueous solubility of the encapsulated therapeutic agent, all while preserving its therapeutic potency. The radiotherapy notably augments the population of Dendritic cells (DCs) and bolsters the presentation of antigens to the tumor cells. Moreover, the administration of GA induces modifications in the tumor's immune microenvironment and escalates the fraction of CD8+ T cells. Within the context of the mouse CRLM model, the amalgamation of M-PLGA@GA with low-dose radiotherapy and immunotherapy markedly attenuates the pace of tumor proliferation and extends the survival of mice. Conclusions Our findings propose that a novel therapeutic regimen combining radiotherapy, immunotherapy, and Nanoparticle gambogic acid can effectively impede tumor progression in the mouse model of CRLM. Therefore, our study provides novel insights into the role of combined antitumor therapy on innate and adaptive antitumor immunity modulation for CRLM.
研究领域:
肿瘤学
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纳米医学
·
放射治疗学
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免疫学
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药理学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 17
·4757-4766
·
IF 6.183
Jing Zhang,Dan Liu,Jiale Liu,Yanfeng Han,Haiyan Xu,Xigang Leng,Deling Kong,Lanxia Liu
Combined blockades of CTLA-4 and PD-1 can yield better overall complementary clinical outcomes than individual blockades, but the response rates are still relatively low. To investigate the anti-tumor effects of various combined strategies, we designed various spherical nucleotide nanoparticles (SNPs) loaded with CTLA-4 aptamer (cSNPs), PD-1 siRNA (pSNPs) or both (hybrid SNPs, or hSNPs). The results demonstrated that hSNPs could promote significantly stronger anti-tumor immune responses in a nonredundant fashion than the mixture of pSNPs and cSNPs (pSNPs & cSNPs). We reasoned that this is because all individual immune cells could receive both CTLA-4 and PD-1 blockades when they engulfed hSNPs, but it is much less likely that individual immune cells could receive both CTLA-4 and PD-1 blockades as many of them may not take both pSNPs and cSNPS from pSNPs & cSNPs. Further results revealed that the synergistic immune stimulatory effects of CTLA-4 and PD-1 blockades in the form of hSNPs were at least partly through regulating the immune suppressive function of both Tregs and TIM3+ exhausted-like CD8 T cells and allowing effector T cells to expand. This mechanism is not identical to earlier reported mechanisms of CTLA-4 and PD-1 blockades.
研究领域:
癌症免疫治疗
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纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2021
·
IF 8.947
Xuan Zhang,Yan Zhang,Haiping Zheng,Yufeng He,Honglin Jia,Liyuan Zhang,Chunjie Lin,Shuang Chen,Junfeng Zheng,Qunfang Yang,Tao Liu,Xichun Pan,Haigang Zhang,Chenhui Wang,Lei Ren,Wenjun Shan
Metastasis is the leading cause of death in cancer patients. Eliciting anti-tumor immune responses against lung metastasis is hindered by the immunosuppressive microenvironment. This study explored a biomimetic nanoformulation, comprising a nanovaccine (OP) that delivers tumor antigens and adjuvants spatially and temporally in a virus-like manner, and a pulmonary surfactant-biomimetic liposome with an immunomodulator, JQ1 (PS-JQ1). The findings of this study showed that intratracheal administration of OP+PS-JQ1 activated lung immune cells without concomitant excess inflammation, enhanced tumor antigen cross-presentation, generated a significantly high antigen-specific CD8 + T cell response, and reshaped the immunocellular composition in B16 melanoma tumor-bearing lung. OP+PS-JQ1 nanoformulation exhibited a striking immunotherapeutic efficacy, induced local and systemic tumor suppression, improved survival of mice, initiated immune memory that prevents recurrence of secondary tumors. This stable and nontoxic nanoformulation provides a simple, flexible, and robust strategy for augmenting anti-tumor immunity for metastatic cancer. Statement of significance Egg glue proteins are produced by female insects, which can make the eggs firmly attached to the oviposition sites, not affected by wind and rain. However, genes encoding insect egg glue proteins have not yet been reported, and the molecular mechanism underpinning their adhesion is still unknown. Our study makes a significant contribution to the literature as it identifies the sequence, structure, adhesive property , and mechanism of silkworm egg glue protein. Furthermore, it outlines key insights into the structure-function relationships associated with egg glue proteins. We believe that this paper will be of interest to the readership of your journal as it identifies the first complete sequence of insect egg glue proteins, thereby highlighting their potentials future applications in both the biomedical and technical fields.
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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生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Jiqian Zhang,Shasha Zhu,Mingxu Zhao,Mengni Zhou,Xiaoling Zhu,Xin Qing,Zhilai Yang,Pengfei Wei,Guoying Zhang,Weiling He,Yongqiang Yu,Xuesheng Liu
Rationale: Tumor ablation can cause severe pain to patients, but there is no satisfactory means of analgesia available. In addition, recurrence of residual tumors due to incomplete ablation threatens patient safety. Photothermal therapy (PTT), a promising approach for tumor ablation, also faces the aforementioned problems. Therefore, developing novel photothermal agents that can efficiently relieve PTT-associated pain and potentiate the PTT efficacy are urgently needed. Methods: The Pluronic F127 hydrogel doped with indocyanine green (ICG) was served as photothermal agent for PTT. Mouse model that inoculation of tumor near the sciatic nerve was constructed to assess the PTT-evoked pain. Subcutaneous and sciatic nerve vicinal tumor-bearing mice were used to test the efficacy of PTT. Results: PTT-evoked pain depends on an increase in tumor temperature and is accompanied by the activation of TRPV1. A simple introduction of local anesthetic (LA) ropivacaine into ICG-loaded hydrogels relieves PTT-induced pain and exerts long-lasting analgesia compared with opioid analgesia. More interestingly, ropivacaine upregulates major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-doped with ropivacaine, TLR7 agonist imiquimod and ICG was rationally designed. In the hydrogel system, imiquimod primes tumor-specific CD8 + T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8 + T cells through upregulating MHC-I. Consequently, the hydrogel maximumly increases CD8 + T cells infiltration into tumor and potentiates PTT efficacy. Conclusion: This study for the first time provides an LA-dopped photothermal agents for painless PTT and innovatively proposes that a LA can be used as an immunomodulator to potentiate the PTT efficacy.
研究领域:
癌症治疗
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生物医学工程
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药学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Xin Long,Anna Dai,Teng Huang,Wenhao Niu,Luoxia Liu,Hui Xu,Tao Yin,Tian’an Jiang,Shuguo Sun,Ping Lei,Chun Li,Xiaohua Zhu,Jun Zhao
Pancreatic ductal adenocarcinoma (PDAC) is an abysmal disease refractory to most standard therapies. Irreversible electroporation (IRE) is a local ablative technique for the clinical treatment of solid tumors, including locally advanced and unresectable PDAC, by intratumorally delivering high-intensity electric pulses to permanently disrupt cell membranes and induce cell death. But the distribution of electric field is uneven within the tumor, and in some regions, tumor cells only experience temporary perturbation to their cell membrane, a phenomenon denoted as reversible electroporation (RE). These tumor cells may survive and therefore are the main culprit of tumor relapse after IRE. We herein showed that RE, although not killing tumor cells, induced DNA double-strand breaks and activated DNA damage repair (DDR) responses. Using reactive oxygen species-sensitive polymeric micelles coloaded with Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM), the resultant nanoformulation (M-TK-OA) disrupted both homologous recombination and nonhomologous end joining signaling of the DDR response and impaired colony formation in pancreatic cancer cells after RE. The combination of IRE and M-TK-OA significantly prolonged animal survival in both subcutaneous and orthotopic murine PDAC models and elicited CD8+ T cell-mediated antitumor immunity with a sustained antitumor memory. The efficacy of combined IRE and M-TK-OA treatments was partially attributed to the activation of cyclic GMP-AMP synthase-stimulator of interferon genes innate immune responses. Our study suggests that dual inhibition of PARP and ATM with nanomedicine is a promising strategy to enhance the pancreatic cancer response to IRE.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2020
·Vol. 16
·期 52
·2004879
·
IF 11.459
Liang Zhao,Yingli Luo,Qiaoyi Huang,Ziyang Cao,Xianzhu Yang
Blocking immune checkpoint pathways with an antibody or small interfering RNA (siRNA) has become a promising method to reactivate antitumor responses for cancer treatment. However, both blockade strategies achieve only temporary inhibition of these immune checkpoints. Herein, a photoswitched CRISPR/Cas9 system for genomic disruption of the PD-L1 gene is developed to achieve permanent blockade of the PD-1/PD-L1 pathway; this system is constructed by using a photoactivated self-degradable polyethyleneimine derivative and the plasmid pX330/sgPD-L1 (expression of the Cas9 protein and single-guide RNA targeting PD-L1). Under light irradiation, this photoswitched CRISPR/Cas9 system efficiently genetically disrupts the PD-L1 gene in not only bulk cancer cells but also cancer stem-like cells. As a result, the photoswitched CRISPR/Cas9 system significantly increases the infiltration of CD8 + T cells into tumor tissue, leading to effective activation of a T cell-mediated antitumor response against cancer cells and cancer stem-like cells. This study provides an alternative strategy to block the PD-1/PD-L1 pathway for efficacious immune checkpoint therapy.
研究领域:
癌症生物学
·
分子生物学
·
免疫学
·
基因工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Lu Ye,Wei Lv,Weichong He,Shengnan Li,Zhiyi Min,Le Gong,Qi Zhang,Chuanhui Teng,Shanbo Sun,Lingyan Lv,Yi Guo,Hongliang Xin
Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages through upregulating anti-phagocytosis molecule CD47, which binds to the signal regulatory protein alpha (SIRPα) of macrophages. Specifically, blocking the CD47-SIRPα pathway is a potential strategy for post-resection glioma treatment. In addition, the anti-CD47 antibody (α-CD47) in combination with temozolomide (TMZ) caused an enhanced pro-phagocytic effect due to the TMZ not only destroying DNA but also inducing endoplasmic reticulum stress response of glioma cells. However, the obstruction of the blood-brain barrier makes systemic combination therapy not ideal for post-resection glioma treatment. Herein, we designed a temperature-sensitive hydrogel system based on a moldable thermosensitive hydroxypropyl chitin (HPCH) copolymer to encapsulate both α-CD47 and TMZ as α-CD47& [email protected] for in situ postoperative cavity administration. Through the in vitro and in vivo evaluations, α-CD47& [email protected] significantly inhibited glioma recurrence post-resection through enhancement of pro-phagocytosis of macrophages, recruitment, and activation of CD8 + T cells and NK cells.
研究领域:
肿瘤学
·
药理学
·
生物医学工程
·
免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2021
·
IF 15.881
Jiaqiang Xiong,Meng Wu,Jilei Chen,Yaofa Liu,Yurou Chen,Guanlan Fan,Yanyan Liu,Jing Cheng,Zhenhua Wang,Shixuan Wang,Yi Liu,Wei Zhang
Cell-membrane-coated nanoparticles are widely studied due to their inherent cellular properties, such as immune escape and homologous homing. A cell membrane coating can also maintain the relative stability of nanoparticles during circulation in a complex blood environment through cell membrane encapsulation technology. In this study, we fused a murine-derived ID8 ovarian cancer cell membrane with a red blood cell (RBC) membrane to create a hybrid biomimetic coating (IRM), and hybrid IRM camouflaged indocyanine green (ICG)-loaded magnetic nanoparticles (Fe3O4-ICG@IRM) were fabricated for combination therapy of ovarian cancer. Fe3O4-ICG@IRM retained both ID8 and RBC cell membrane proteins and exhibited highly specific self-recognition of ID8 cells in vitro and in vivo as well as a prolonged circulation lifetime in blood. Interestingly, in the bilateral flank tumor model, the IRM-coated nanoparticles also activated specific immunity, which killed homologous ID8 tumor cells but had no effect on B16-F10 tumor cells. Furthermore, Fe3O4-ICG@IRM showed synergistic photothermal therapy, resulting in the release of whole-cell tumor antigens by photothermal-induced tumor necrosis, which further enhanced antitumor immunotherapy for primary tumor and metastatic tumor by activating CD8+ cytotoxic T cells and reducing regulatory Foxp3+ T cells. Together, the biomimetic Fe3O4-ICG@IRM nanoparticles showed synergistic photothermal-immunotherapy for ovarian cancer.
研究领域:
纳米技术
·
肿瘤学
·
生物医学工程
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER SCIENCE
·
2018
·Vol. 109
·期 9
·2677-2686
·
IF 4.372
Yilin Zhao,Qi Shao,Haitao Zhu,Haiyuan Xu,Wei Long,Bin Yu,Lining Zhou,Huaxi Xu,Yan Wu,Zhaoliang Su
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells which consist of 2 subsets: granulocytic MDSC (G-MDSC) and monocytic MDSC (M-MDSC). MDSC expand in tumor-bearing hosts and contribute to immunotherapeutic resistance by remarkably blocking effector T-cell activation via different mechanisms. Resveratrol (RSV) is a polyphenol and it has been widely used for its various health benefits. However, the underlying mechanism of its anti-tumor properties remains unclear. In this study, a transplantable mouse model was used to investigate the effects of RSV on MDSC. The results showed that RSV ameliorated tumor development by decreasing G-MDSC accumulation, impairing its suppressive ability on CD8 + T cells and promoting M-MDSC differentiation into CD11c + and F4/80 + cells. Our results indicated that RSV should be considered as a modular of MDSC suppressive function and that RSV is a novel booster for tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Benjin Chen,Liang Xiao,Wanni Wang,Lingling Xu,Yechun Jiang,Guoqiang Zhang,Lin Liu,Xiaohu Li,Yongqiang Yu,Haisheng Qian
Radiotherapy efficacy was greatly limited by hypoxia and overexpression of glutathione (GSH) in the tumor microenvironment (TME), which maintained the immunosuppressive microenvironment and promoted DNA repair. In this work, 4T1 cell membrane-coated Bi2–xMnxO3 nanospheres have been achieved via a facile protocol, which showed enhanced therapeutic efficacy for a combination of radiotherapy and immunotherapy. Bi2–xMnxO3 nanospheres showed appreciable performance in generating O2 in situ and depleting GSH to amplify DNA damage and remodel the tumor immunosuppressive microenvironment, thus enhancing radiotherapy efficacy. Cancer cell membrane-coated Bi2–xMnxO3 nanospheres (T@BM) prolonged blood circulation time and enriched the accumulation of the materials in the tumor. Meanwhile, the released Mn2+ could activate STING pathway-induced immunotherapy, resulting in the immune infiltration of CD8+ T cells on in situ mammary tumors and the inhibition of pulmonary nodules. As a result, approximately 1.9-fold recruitment of CD8+ T cells and 4.0-fold transformation of mature DC cells were observed compared with the phosphate-buffered saline (PBS) group on mammary tumors (in situ). In particular, the number of pulmonary nodules significantly decreased and the proliferation of pulmonary metastatic lesions was substantially inhibited, which provided a longer survival period. Therefore, T@BM exhibited great potential for the treatment of 4T1 tumors in situ and lung metastasis.
研究领域:
癌症治疗
·
纳米医学
·
免疫学
·
放射生物学
✓ 已验证
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）