Science China-Chemistry
·
2024
·
IF 10.4
Yang Shuguang,Hu Lijun,Xiao Hong,Xiao Zecong,Shuai Xintao
Enhancing the concentration of exogenous molecular drugs within the tumor microenvironment through enzyme-catalyzed polymerization presents a novel strategy for cancer therapy. Nonetheless, the optimization of the catalytic efficiency is often impeded by the inefficient expression of enzymes. Herein, we reported a self-amplifying fluorescent molecular probe, Bis-HTP-ICG, for photodynamic therapy (PDT) and subsequent PDT-induced immunoreaction. The Bis-HTP-ICG probe possesses a noticeable enzyme-catalyzed polymerization facilitated by myeloperoxidase (MPO), a crucial enzyme secreted by neutrophils at inflammation sites. Upon exposure to laser irradiation, Bis-HTP-ICG showed a high PDT efficacy, inducing an acute inflammatory response that stimulates further recruitment of neutrophils and then elevated MPO secretion. The heightened level of MPO enhances the accumulation of the Bis-HTP-ICG via self-polymerization or binding with intratumoral proteins following MPO enzyme catalysis, instigating a self-amplifying chain reaction cycle involving Bis-HTP-ICG, neutrophils and MPO. Meanwhile, PDT efficiently incites immunogenic cell death (ICD) in tumor cells, initiating an anti-tumor immune response including dendritic cells (DCs) maturation, T cell proliferation and reprogramming of tumor-associated neutrophils (TANs). This work portrays a promising strategy for self-amplification of fluorescent molecular probes through adjustable enzyme levels, potentially offering a unique avenue to enhance the tumor accumulation of molecular drugs for improved tumor therapy.
研究领域:
癌症治疗
·
免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
高影响因子
Small
·
2023
·
IF 13.3
Xuehua Long,Huiqi Wang,Jianqin Yan,Yifei Li,Xue Dong,Sijia Tian,Yong Sun,Kui Luo,Bin He,Yan Liang
Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol–polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.
研究领域:
癌症研究
·
纳米技术
·
免疫治疗
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Yu-Xiang Ge,Tai-Wei Zhang,Lei Zhou,Wang Ding,Hai-Feng Liang,Zhi-Chao Hu,Qin Chen,Jian Dong,Feng-Feng Xue,Xiao-Fan Yin,Li-Bo Jiang
Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, [email protected] @PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH , which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8 + T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2022
·
IF 5.589
Qiangwei Liang,Yang Lan,Yifan Li,Yongjin Cao,Juan Li,Yanhua Liu
Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG- b -PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG- b -PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG- b -PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG- b -PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration , concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG- b -PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.
研究领域:
药学
·
肿瘤学
·
免疫治疗
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Liming Gui,Kaiwen Chen,Jingjing Yan,Ping Chen,Wei-Qiang Gao,Bin Ma
The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
研究领域:
癌症研究
·
免疫学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2023
·Vol. 35
·期 14
·2211579
·
IF 29.4
Jia Ma,Daoxia Guo,Xiaoyuan Ji,Yanfeng Zhou,Chang Liu,Qian Li,Jiye Zhang,Chunhai Fan,Haiyun Song
Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. In this work, it is found that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near-infrared irradiation to reinforce ICD. A hydrogel co-delivering cancer-cell-targeting CuS NPs and immunosuppressive-cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention i further fabricated. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse, and metastasis. This study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu.
研究领域:
癌症研究
·
免疫疗法
·
纳米医学
·
代谢工程
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Jing Zhang,Di Zhang,Qian Li,Yue Jiang,Aixin Song,Zhonghao Li,Yuxia Luan
Potentiating systemic immunity against breast cancer is in the most urgent demand as breast cancer is less sensitive to immune checkpoint blockade. Although phototherapy and some chemotherapy can trigger immunogenic cell death (ICD) for T cell-mediated antitumor immune response, their immunotherapy efficacy is severely restricted by insufficient phototherapeutic capability and severe multidrug resistance (MDR). Inspired by both the hypersensitivity to phototherapy and the key role of MDR for mitochondria, a rationally engineered immunity amplifier via mitochondria-targeted photochemotherapeutic nanoparticles was, for the first time, achieved to fight against low-immunogenic breast cancer without additional immune agents. The newly synthesized task-specific mitochondria-targeted IR780 derivative (T780) was integrated with chemotherapeutic doxorubicin (DOX) to form multifunctional nanoparticles via an assembling strategy along with bovine serum albumin (BSA) as a biomimetic corona (BSA@T780/DOX NPs). The in situ enhancement in both phototherapy and MDR reversal by targeting mitochondria with BSA@T780/DOX NPs boosted highly efficient ICD toward excellent antitumor immune response. The newly developed strategy not only eradicated the primary tumor but also eliminated the bilateral tumors efficiently, as well as preventing metastasis and postsurgical recurrence, demonstrating great interest for fighting against low-immunogenic breast cancer.
研究领域:
癌症研究
·
纳米技术
·
免疫疗法
·
药物科学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-14
·
IF 9.429
Deng Bo,Ma Bing,Ma Yingying,Cao Pei,Leng Xigang,Huang Pengyu,Zhao Yuanyuan,Ji Tianjiao,Lu Xueguang,Liu Lanxia
Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8 + and CD4 + T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect. Graphical Abstract
研究领域:
癌症治疗
·
药物递送系统
·
免疫疗法
·
纳米医学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Yunjian Yu,Jie Li,Boyi Song,Zhuang Ma,Yufei Zhang,Haonan Sun,Xiaosong Wei,Yayun Bai,Xueguang Lu,Peng Zhang,Xinge Zhang
Checkpoint inhibitors, such as antibodies blocking the PD-1/PD-L1 pathway, are among the most promising immunotherapies to treat metastatic cancers, but their response rate remains low. In addition, the usage of monoclonal antibodies as checkpoint inhibitors is associated with a series of drawbacks. Herein, an all synthetic nanoparticle with PD-L1 blockade capability is developed for cancer photothermal-immunotherapy. The polymeric nanoparticle integrates photothermal treatment, antitumor vaccination, and PD-1/PD-L1 blockade in a single system to augment the antitumor efficacy. In a CT26 bilateral tumor model, intravenously injected nanoparticles accumulate in tumor sites and mediate strong photothermal effects, eradicate the NIR treated primary tumors and elicit strong antitumor immunity by inducing immunogenic cell death (ICD). Growth of the untreated distant tumors is also suppressed due to the synergies of systemic antitumor immune activation and PD-L1 blockade. Our strategy offers a simple but promising approach for the treatment of metastatic cancer.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Chaonan Shi,Minglong Chen,Xiaodie Li,Yanping Fu,Dan Yang,Ting Wen,Wanchen Zhao,Ying Sun,Wenhao Wang,Chao Lu,Qiaoli Wu,Chuanbin Wu,Xin Pan,Guilan Quan
Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy .
研究领域:
癌症免疫疗法
·
药学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Yilu Zheng,Gareth R Williams,Ran Hu,Sen Tong,Jianxiang Xu,Tong Wang,Yanyan Zhang,Junzi Wu,Fan Li,Yingyu Cai,Li-Min Zhu
Background: The development of selective formulations able to target and kill tumor cells without the application of external energy has shown great promise for anti-tumor therapy.Methods: Here, we report a “nanobomb” that explosively increases Ca content within cells. It can selectively release Ca2+ and generate H2O2 in the tumor microenvironment (TME) by acid-triggered degradation of the two-layer protective shell (ie, unlocking the “double-lock”). This material, termed CaO2@ZIF8:CUR@PAA, comprises a CaO2 core coated with the ZIF-8 framework, which was then loaded with curcumin (CUR) and coated again with polyacrylic acid (PAA).Results: Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO2@ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca2+, and H2O2. CUR can promote the release of Ca2+ from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca2+, and accumulates a large amount of Ca2+ intracellularly together with exogenous Ca2+ (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous H2O2 causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO2@ZIF8:CUR@PAA NPs can induce cell S cycle arrest and apoptosis to inhibit tumor multiplication and growth. Oxidative damage-triggered immunogenic cell death (ICD) in turn leads to the polarization of macrophages to the M1 phenotype, inducing immunogenic cell death and inhibiting tumor cell proliferation and metastasis.Discussion: The acid two-step unlocking nanoplatform is a therapeutic modality that combines calcium storm and oxidative damage. The mode triggers apoptosis leading to ICD of tumor cells. The material induces cycle blockade during treatment to inhibit cell proliferation. Robust in vitro and in vivo data demonstrate the efficacy of this approach and CaO2@ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.Highlights: - A new calcium accumulation nanoplatform plays a role in activate antitumor immunity.- Double-locked structure slows down the premature decomposition of CaO2.- The platform allows Ca2+ and H2O2 to accumulate in tumor cells.- This leads to mitochondrial dysfunction, apoptosis, and M1 macrophage polarization.- Potent anti-tumor effects are seen both in vitro and in vivo.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Xingyu Zhang,Chengyu Shi,Qiao Liu,Yuting Zhong,Lipeng Zhu,Yuetao Zhao
Combination of immunotherapy and photothermal therapy (PTT) provides a promising therapeutic performance for tumors. However, it still faces negative feedback from suppressive factors such as adenosine. Herein, we developed a new nanodrug that can combine adenosine blockade and ferroptosis to promote the photoimmunotherapy of triple negative breast cancer (TNBC). The nanodrug, named CuS-PEG@Apt, was constructed via the modification of copper sulfide (CuS) nanoparticles with adenosine aptamer and PEG. CuS-PEG@Apt could be effectively enriched in the tumor site and locally generate a strong photothermal effect, directly ablating tumors and inducing immunogenic death (ICD). On the other hand, the aptamers could block the adenosine pathway to inhibit the immune suppression by adenosine, which further promoted the anti-tumor immunity. Moreover, the CuS nanoparticles could consume GSH and inhibit GPX4 to cause the ferroptosis of tumor cells. Collectively, CuS-PEG@Apt achieved potent efficacy of tumor suppression via the combination of PTT, immune activation and ferroptosis, representing an appealing platform for TNBC treatment.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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