The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity DOI Creative Commons
J. K. Lim, Ryan Rodriguez, Katherine Williams

et al.

Cancer Immunology Research, Journal Year: 2024, Volume and Issue: 12(6), P. 663 - 672

Published: March 15, 2024

Abstract The DNA exonuclease three-prime repair 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to production type I IFNs. As tumor cells are prone aberrant accumulation, we hypothesized that they critically dependent on TREX1 activity limit their immunogenicity. Here, show cells, restricts spontaneous pathway, subsequent induction a IFN response. result, deficiency compromised vivo growth mice. This delay depended functional immune system, systemic signaling, tumor-intrinsic cGAS expression. Mechanistically, loss drove CD8+ T NK prevented T-cell exhaustion, remodeled an immunosuppressive myeloid compartment. Consequently, combined with T-cell–directed checkpoint blockade. Collectively, conclude essential immunogenicity, targeting this remodels microenvironment enhances antitumor immunity itself combination T-cell–targeted therapies. See related article Toufektchan et al., p. 673

Language: Английский

Copper‐Based Composites Nanoparticles Improve Triple‐Negative Breast Cancer Treatment with Induction of Apoptosis‐Cuproptosis and Immune Activation DOI
Ning Wang, Yichao Liu,

Dezhou Peng

et al.

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(28)

Published: July 12, 2024

The synergistic effect of apoptosis and cuproptosis, along with the activation immune system, presents a promising approach to enhance efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX glutathione (GSH)-responsive PEG-DTPA-SS-CPT. These self-assembled chelated Cu2+ prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), Cu2+. elevated levels ROS GSH in TNBC cells disrupted structure, leading release Cu+, DOX, CPT depletion GSH. DOX triggered immunogenic cell death (ICD) cells. Simultaneously, downregulated expression copper transporting ATPase 2 (ATP7B), causing significant accumulation ions This further induced aggregation lipoylated dihydrolipoamide S-acetyltransferase (DLAT) downregulation iron-sulfur (Fe-S) cluster proteins, ultimately cuproptosis ICD TNBC. In vitro vivo experiments confirmed activated demonstrating strong anti-tumor capabilities. Moreover, exhibited an excellent biosafety profile. Overall, this study provides strategy for effective therapy.

Language: Английский

Citations

18
Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives DOI Creative Commons
Chenliang Zhang, Tingting Huang, Liping Li

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 16, 2024

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and loss iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress triggering death. Recently, has garnered significant interest tumor research due to its potential as crucial therapeutic strategy against cancer. In this review, we summarized cellular molecular mechanisms relationship other types Additionally, reviewed current drugs or strategies available induce cells, including Cu ionophores, small compounds, nanomedicine. Furthermore, targeted metabolism specific regulatory genes cancer therapy enhance sensitivity cuproptosis. Finally, discussed feasibility targeting overcome chemotherapy immunotherapy resistance suggested future directions. This study that could open new avenues for developing therapy.

Language: Английский

Citations

18
Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy DOI Creative Commons

Li Sun,

Hongbo Gao, Han Wang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(12)

Published: Jan. 15, 2024

Abstract Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance pathway. Herein, multifunctional ZIF‐8@MnO 2 nanoparticles are constructed degrade mutp53 and facilitate The synthesized can release Zn 2+ Mn cancer cells induce oxidative stress cytoplasmic leakage fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, released induces variable degradation multifarious mutants through proteasome ubiquitination, which alleviate inhibitory effects on In addition, further increases sensitivity cGAS dsDNAs as immunostimulatory signals. Both vitro vivo results demonstrate that effectively promotes synergizes with PD‐L1 checkpoint blockades, leading remarkable regression local tumors well distant metastases breast cancer. This study proposes an inorganic metal ion‐based nanoplatform enhance cGAS‐STING‐mediated immunotherapy, especially those expression.

Language: Английский

Citations

17
Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity DOI Creative Commons
Hao Zhou, Wenkan Zhang, Hengyuan Li

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 17, 2024

Bone is one of the most common sites tumor metastases. During last step bone metastasis, cancer cells colonize and disrupt matrix, which maintained mainly by osteocytes, abundant in microenvironment. However, role osteocytes metastasis still unclear. Here, we demonstrated that transfer mitochondria to metastatic trigger cGAS/STING-mediated antitumor response. Blocking specifically knocking out mitochondrial Rho GTPase 1 ( Rhot1 ) or mitofusin 2 Mfn2 impaired immunogenicity consequently resulted progression toward matrix. These findings reveal protective against transferring potentially offer a valuable therapeutic strategy for preventing metastasis.

Language: Английский

Citations

17
Regulation of cGAS–STING signalling and its diversity of cellular outcomes DOI
Zhengyin Zhang, Conggang Zhang

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

Citations

5
Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung DOI Creative Commons
Tianchuan Zhu, Yuchen Xiao, Zhenxing Chen

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with STING agonist cGAMP (aPD-L1 NVs@cGAMP) remodel and thereby enhance CAR-T cell activity. Following pulmonary delivery, nanovesicles rapidly accumulate in lung selectively deliver agonists PD-L1-overexpressing via PD-1/PD-L1 interaction. This targeted delivery effectively avoids systemic inflammation poor cellular uptake that plague free agonists. Internalized trigger signaling induce interferon responses, which diminish populations such as myeloid-derived suppressor promote infiltration. Importantly, anti-PD-L1 single chain variable fragment on surface blocks PD-L1 upregulation induced prevents exhaustion. In both orthotopic cancer metastasis model, combined therapy aPD-L1 NVs@cGAMP potently inhibits growth recurrence. Therefore, is expected serve effective enhancer improve The hindered Here authors report design characterization inhalable cGAMP, showing enhanced activity models.

Language: Английский

Citations

3
Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy DOI
Qiao Yu,

Shumin Sun,

Nailin Yang

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and subsequent release DNA (mtDNA), which is anticipated to activate cGAS-STING pathway, thereby augmenting antitumor immune response. However, challenges lie in effectively triggering cancer cells subsequently enhancing activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators cobalt fluoride (CoF2) nanocatalysts for catalytic metalloimmunotherapy. CoF2 a semiconductor structure enzyme-like activity generated substantial amount reactive oxygen species (ROS) under stimulation by endogenous H2O2 exogenous ultrasound. Importantly, discovered that Co-based nanomaterials themselves induce cells. Therefore, initially acted as inducers, caspase-1/GSDMD-dependent via Co2+ ROS, leading mtDNA release. Subsequently, were further utilized STING agonists specifically capable detecting pathway. These cascade events triggered robust response, modulating immunosuppressive tumor microenvironment into an immune-supportive state, providing favorable support therapy. This innovative strategy not only significantly impeded growth primary but also elicited response augment efficacy checkpoint inhibitors preventing distant progression. Overall, this study proposed self-cascade activating amplifying pathway specificity mediated pyroptosis, representing valuable avenue future

Language: Английский

Citations

3
Metal Ion Signaling in Biomedicine DOI Creative Commons
Raphaël Rodriguez, Sebastian Müller, Ludovic Colombeau

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species defined by their genomes, and differences between individuals within a given species directly result from variations in genetic codes. While alterations give rise to disease-causing acquisitions cell identities, it is now well-established biochemical imbalances also lead cellular dysfunction diseases. Specifically, nongenetic chemical events orchestrate metabolism transcriptional programs govern functional identity. Thus, signaling, which broadly defines the conversion extracellular signals into intracellular changes, contribute acquisition diseased states. Metal ions exhibit unique properties be exploited cell. For instance, metal maintain ionic balance cell, coordinate amino acid residues or nucleobases altering folding function biomolecules, catalyze reactions. metals essential signaling effectors normal physiology disease. Deciphering ion challenging endeavor illuminate pathways targeted for therapeutic intervention. Here, we review key processes where play roles describe how targeting has been instrumental dissecting biochemistry this led development effective strategies.

Language: Английский

Citations

2
Dendritic cell maturation in cancer DOI
Chang Moon, Meriem Belabed, Matthew D. Park

et al.

Nature reviews. Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

Citations

2
Adjuvant physiochemistry and advanced nanotechnology for vaccine development DOI
Hongze Ren,

Wencong Jia,

Yujie Xie

et al.

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(15), P. 5172 - 5254

Published: Jan. 1, 2023

This review provides an introduction of basic principles adjuvanted human vaccines in clinics and summarizes emerging nanotechnology adjuvants vaccine development against cancer infectious diseases.

Language: Английский

Citations

37