Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME

Kumar, Vijay; Bauer, Caitlin; Stewart, John H.

doi:10.1186/s12929-023-00942-2

Cited by 11 publications

(8 citation statements)

References 236 publications

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“…47 This process leads to the reactivation of macrophages in response to GBM cells and the subsequent activation of the STING signaling pathway. 48 Most significantly, therapeutic strategies centered around modulation of the innate immune response not only arrest the progression of GBM but also activate the adaptive immune response, effectively suppressing postoperative GBM relapse in patientderived orthotopic xenograft models.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, mtROS induce specific oxidative damage to mtDNA and this damaged mtDNA can escape from GBM cells, serving as a molecular pattern of immunogenic damage-associated molecules for M1 macrophages . This process leads to the reactivation of macrophages in response to GBM cells and the subsequent activation of the STING signaling pathway . Most significantly, therapeutic strategies centered around modulation of the innate immune response not only arrest the progression of GBM but also activate the adaptive immune response, effectively suppressing postoperative GBM relapse in patient-derived orthotopic xenograft models.…”

Section: Discussionmentioning

confidence: 99%

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Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

Zhang,

Xi,

Zhang

et al. 2024

ACS Nano

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Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood−brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

Zhang,

Xi,

Zhang

et al. 2024

ACS Nano

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“…Other innate immune cells, such as natural killer (NK) cells and neutrophils, are also increased in TME, with enhanced antitumor responses after activation of the STING pathways [ 30 , 31 ]. Immunosuppressive cells also convert their characteristics by activating STING, such as reducing myeloid-derived suppressor cells and repolarizing macrophages [ 32 , 33 ]. Therefore, STING-mediated production of IFNs reforms the immunogenicity of TME and increases the antitumor immune response.…”

Section: Overview Of Cgas-sting Pathways In Mediating Immune Responsesmentioning

confidence: 99%

Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy

Chen,

Xu,

et al. 2024

Biomark Res

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The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.

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“…It is crucial to note that cGAS activation is responsible for producing more type 1 IFNs than any other cytosolic PRR (e.g., TLR7 and TLR9) recognizing cytosolic dsDNA. We have described the details of cGAS/STING signaling and its regulation elsewhere [30,56,109,110].…”

Section: Cgas/sting Signaling Pathway In Cellular and Immune Homeosta...mentioning

confidence: 99%

cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis

Kumar,

Stewart

2024

IJMS

Self Cite

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Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, and RLRs are well-characterized PRRs of the host immune system. cGLRs have been recently identified as PRRs. In humans, the cGAS/STING signaling pathway is a part of cGLRs. cGAS recognizes cytosolic dsDNA as a PAMP or DAMP to initiate the STING-dependent immune response comprising type 1 IFN release, NF-κB activation, autophagy, and cellular senescence. The present article discusses the emergence of cGLRs as critical PRRs and how they regulate immune responses. We examined the role of cGAS/STING signaling, a well-studied cGLR system, in the activation of the immune system. The following sections discuss the role of cGAS/STING dysregulation in disease and how immune cross-talk with other PRRs maintains immune homeostasis. This understanding will lead to the design of better vaccines and immunotherapeutics for various diseases, including infections, autoimmunity, and cancers.

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Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME

Cited by 11 publications

References 236 publications

Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy

cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis

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