Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

Xiong, Hong‐Gang; Ma, Xianbin; Wang, Xiaolong; Su, Wen; Wu, Lei; Tian, Ziqiang; Xu, Zhigang; Sun, Zhi‐Jun

doi:10.1002/adfm.202100007

Cited by 53 publications

(25 citation statements)

References 78 publications

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“…According to the previous literature, pyroptosis is favorable for inducing antitumor immune responses via the release of enough DAMPs. [18] To assess the antitumor efficacy of COF-909-Cu in vivo, a 4T1-tumor-bearing mouse animal model was established, and the treatment schedule is displayed in Figure 5A. The results showed that almost all the tumors could be eliminated (Figure S28, Supporting Information) with normal spleen size after treatment with COF-909-Cu+Laser (Figures 5B,C and Figure S29, Supporting Information), uncovering the excellent antitumor efficacy of COF-909-Cumediated pyroptosis.…”

Section: Activity (Figuresmentioning

confidence: 99%

Engineering Multienzyme‐Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity

et al. 2022

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Such porous materials not only effectively avoid unwanted active site accumulation induced quenching (ACQ) and offer sufficient contact with guest molecules to favor their exchange and diffusion, but more importantly, finely tune their band energy and optical properties via formation of covalently linked crystalline domains. [2] In this study, this strategy was utilized to form a series of multienzyme-mimicking covalent organic frameworks by decorating metal ions (Cu, Fe and Ni) into the COF backbone, where their optical properties, including band energy, lifetime, and lightabsorption properties, were finely tuned to achieve excellent enzyme-mimicking catalytic performance, including superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPx) activities. As a result, one member, COF-909-Cu was revealed to be a good pyroptosis inducer for boosting cancer immunotherapy for the first time.As a form of noninflammatory programmed cell death (PCD), the efficacy of apoptosis is usually limited due to the existence of apoptosis resistance in cancer cells, leading to unsatisfactory therapeutic performance. [3] In contrast to apoptosis, pyroptosis and ferroptosis are immunogenic PCD and are recently proven to be a powerful strategy to combat cancer, owing to their favorable ability to prime antitumor immune responses by releasing sufficient danger-associated molecular patterns (DAMPs). [4] Attempts have been made to isolate iron ions into the building block of MOF to facilitate the pyroptosiseliciting process and activate the immune system. [5] Recently, COFs were also utilized as new photosensitizers (PSs) for chemodynamic therapy (CDT)-triggered ferroptosis. [6] The potential of inducing pyroptosis by using COF materials, however, is rarely explored due to the stringent requirement for an acute inflammatory response. Moreover, the hypoxic character in the tumor microenvironment (TME) and limited penetration depth also restrict the reactive oxygen species (ROS) generation efficiency of photodynamic therapy (PDT). [7] CDT, which involves the consumption of intracellular hydrogen peroxide (H 2 O 2 ) to produce hydroxyl radicals (•OH), the most harmful ROS, is promising for eliciting acute inflammatory responses and inducing pyroptosis due to the advantages of not relying The engineering of a series of multienzyme-mimicking covalent organic frameworks (COFs), COF-909-Cu, COF-909-Fe, and COF-909-Ni, as pyroptosis inducers, remodeling the tumor microenvironment to boost cancer immunotherapy, is reported. Mechanistic studies reveal that these COFs can serve as hydrogen peroxide (H 2 O 2 ) homeostasis disruptors to elevate intracellular H 2 O 2 levels, and they not only exhibit excellent superoxide dismutase (SOD)-mimicking activity and convert superoxide radicals (O 2 •− ) to H 2 O 2 to facilitate H 2 O 2 generation, but also possess outstanding glutathione peroxidase (GPx)-mimicking activity and deplete glutathione (GSH) to alleviate the scavenging of H 2 O 2 . Meanwhile, the outstanding photothermal the...

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Section: Activity (Figuresmentioning

confidence: 99%

Engineering Multienzyme‐Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity

et al. 2022

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“…As an inflammatory form of PCD, pyroptosis is a promising strategy for enhancing cancer immunotherapy. Xiong et al designed a GSH-responsive nanomicelles prodrug, composed of the adenosine inhibitor α, β-methylene adenosine 5' diphosphate (AMPCP) and the epigenetic modulator γ-oryzanol (Orz) for tumor therapy, which they termed as AOZN (Figure 5 D) 114 . When AOZN reaches the tumor site, high GSH in the TME triggers AMPCP and Orz release.…”

Section: Inducing Cancer Cell Pyroptosis For Cancer Therapymentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Pyroptosis in inflammatory diseases and cancer

et al. 2022

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Pyroptosis is a lytic and inflammatory type of programmed cell death that is usually triggered by inflammasomes and executed by gasdermin proteins. The main characteristics of pyroptosis are cell swelling, membrane perforation, and the release of cell contents. In normal physiology, pyroptosis plays a critical role in host defense against pathogen infection. However, excessive pyroptosis may cause immoderate and continuous inflammatory responses that involves in the occurrence of inflammatory diseases. Attractively, as immunogenic cell death, pyroptosis can serve as a new strategy for cancer elimination by inducing pyroptotic cell death and activating intensely antitumor immunity. To make good use of this double-edged sword, the molecular mechanisms, and therapeutic implications of pyroptosis in related diseases need to be fully elucidated. In this review, we first systematically summarize the signaling pathways of pyroptosis and then present the available evidences indicating the role of pyroptosis in inflammatory diseases and cancer. Based on this, we focus on the recent progress in strategies that inhibit pyroptosis for treatment of inflammatory diseases, and those that induce pyroptosis for cancer therapy. Overall, this should shed light on future directions and provide novel ideas for using pyroptosis as a powerful tool to fight inflammatory diseases and cancer.

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“…Pretreatment of tumor-bearing mice with DAC increases chemosensitivity by promoting GSDME-mediated pyroptosis 78 . Another DNA methyltransferase inhibitor, γ-oryzanol, upregulates the expression of GSDMD in cancer cells, thus enhancing cancer immunotherapy in animal models 79 . The main remaining question in exploiting these proinflammatory effects is how to increase the efficacy of immunotherapy, and decrease or avoid adverse effects.…”

Section: Pyroptosis and Cancer Therapymentioning

confidence: 99%

“…CD39/CD73-targeting agents have recently entered clinical trials. More recently, we have engineered a bioresponsive nanoparticle that effectively enhances the efficacy of anti-PD-L1 therapy through synergistic effects of pyroptosis and CD73 inhibition 79 .…”

Section: Pyroptosis and Cancer Therapymentioning

confidence: 99%

Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies

2022

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Immune checkpoint blockade (ICB) therapy has recently shown promise in treating several malignancies. However, only a limited number of patients respond to this treatment, partially because of the “immune cold” condition of the tumor immune microenvironment. Pyroptosis is a type of gasdermin-mediated programmed cell death that often leads to inflammation and immune responses. Many studies on the mechanism and function of pyroptosis have led to increasing recognition of the role of pyroptosis in malignant progression and immune therapy. Pyroptosis has the potential to alter the tumor immune microenvironment by releasing tumor-associated antigens, damage-associated molecular patterns, and proinflammatory cytokines, thus leading to intratumoral inflammatory responses, stimulation of tumor-specific cytotoxic T cell infiltration, conversion of “cold” to “hot” tumors, and ultimately improving the efficacy of ICB therapy. Some cancer treatments have been shown to restore anticancer immunosurveillance through the induction of pyroptosis. Therapy promoting pyroptosis and ICB therapy may have synergistic effects in cancer treatment. This review summarizes the mechanisms and roles of pyroptosis in the tumor microenvironment and combination treatment strategies. An improved understanding of the roles of pyroptosis in tumorigenesis, immune evasion, and treatment would aid in the development of therapeutic strategies for malignancies.

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Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

Cited by 53 publications

References 78 publications

Engineering Multienzyme‐Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity

Engineering Multienzyme‐Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity

Pyroptosis in inflammatory diseases and cancer

Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies

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