A Thermosensitive Bi‐Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti‐Tumor Efficacy of Frameshift Neoantigens DOI Creative Commons

Yaohua Ke,

Kai Xin, Yaping Tao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(14)

Published: Feb. 2, 2024

Abstract Tumor‐specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self‐tolerance. Here, a thermosensitive hydrogel (FSP‐RZ‐BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn 2+ (cGAS‐STING designed to promote the of FSPs on murine forestomach (MFC). After peritumoral injection, FSP‐RZ‐BPH behaves as pH‐responsive sustained drug release at sites near effectively transform TME into an inflammatory type. orchestrates innate adaptive immunity activate dendritic cells in tumor‐draining lymph nodes increase number FSPs‐reactive effector memory T ( EM ) 2.9 folds. More importantly, these also exhibit responses nonvaccinated MFC. This epitope spreading effect contributes reduce self‐tolerance maintain long‐lasting anti‐tumor immunity. In MFC suppressive model, achieves 84.8% inhibition rate prolongs survival tumor‐bearing mice with 57.1% complete response rate. As preventive vaccine, can significantly delay growth. Overall, work identifies first time demonstrates bi‐adjuvant effective strategy boost bystander neoantigens.

Language: Английский

Tumor Microenvironment‐Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy DOI
Dan Liu, Shuang Liang,

Kongshuo Ma

et al.

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(6)

Published: Sept. 19, 2023

Abstract Insufficient activation of the stimulator interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits effect cancer immunotherapy. Herein, tumor (TME)‐responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING Toll‐like receptor 4 (TLR4) to augment via TLR4‐mediated nuclear factor‐kappa B stimulation, leading increased secretion type I interferons (i.e., 4.0‐fold enhancement IFN‐β) pro‐inflammatory cytokines promote a specific T cell immune response. Moreover, PMM NPs relieve immunosuppression TME by decreasing percentage regulatory cells, polarizing M2 macrophages M1 type, thus creating an immune‐supportive unleash cascade adaptive Combined with anti‐PD‐1 antibody, synergistic efficacy is achieved in both inflamed colorectal noninflamed metastatic breast models. rechallenging tumor‐free animals homotypic cells induced complete rejection, indicating generation systemic antitumor memory. These TME‐responsive may open new avenue achieve spatiotemporal orchestration activation, providing promising clinical candidate for next‐generation

Language: Английский

Citations

56
Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy DOI
Chengming Qu, Haitao Yuan, Ming Tian

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(5), P. 4019 - 4037

Published: Jan. 22, 2024

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to dense desmoplastic immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective PDAC owing poor selectivity, insufficient penetration, accumulation of photosensitizers in sites. Here, we designed a light-responsive novel nanoplatform targeting the TME through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) locally produce abundant reactive oxygen species (ROS) precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging tumors (fluorescence photoacoustic imaging) but lead apoptosis immunogenic cell death cells via ROS under light excitation, ultimately preventing progression remodeling with increased infiltration T lymphocytes. Combined PD-1 checkpoint blockade, targeted PDT platform showed best antitumor performance markedly extended mice survival. Conclusively, this work integrating Nbs NPs provides strategy target formidable suppression activate immunity, creating possibilities boosting efficacy combination local PDT.

Language: Английский

Citations

23
Tea polyphenols alleviate TBBPA-induced inflammation, ferroptosis and apoptosis via TLR4/NF-κB pathway in carp gills DOI
Ran Xu,

Fu-xin Han,

Hongru Wang

et al.

Fish & Shellfish Immunology, Journal Year: 2024, Volume and Issue: 146, P. 109382 - 109382

Published: Jan. 18, 2024

Language: Английский

Citations

21
A Bioactive Injectable Hydrogel Regulates Tumor Metastasis and Wound Healing for Melanoma via NIR‐Light Triggered Hyperthermia DOI Creative Commons
Xueyi Liu,

Meifang Shen,

Tiejun Bing

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: May 5, 2024

Abstract Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting high recurrence rates patients. Herein, a bioactive injectable hydrogel (BG‐Mn gel ) formed by crosslinking sodium alginate (SA) with manganese‐doped glass (BG‐Mn) is developed as versatile platform anti‐tumor immunotherapy postoperative The incorporation of Mn 2+ within (BG) can activate cGAS‐STING immune pathway to elicit robust response cancer immunotherapy. Furthermore, doping BG endows system excellent photothermal properties, hence facilitating STING activation reversing immune‐suppressive microenvironment. exhibits favorable angiogenic capacity tissue regenerative potential, promotes cell migration vitro. When combining BG‐Mn anti‐PD‐1 antibody (α‐PD‐1) melanoma, it shows enhanced long‐term memory response. Remarkably, upregulate expression genes related blood vessel formation promote skin regeneration when treating full‐thickness wounds. Overall, Gel serves an effective adjuvant therapy regulate

Language: Английский

Citations

20
Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma DOI Creative Commons
Justin Low, Michael C. Brown, Zachary J. Reitman

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(2)

Published: Jan. 15, 2024

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon antitumor T cell responses, efforts to understand therapeutically target STING pathway in have ensued. Relative other types, glioma immune microenvironment harbors few infiltrating cells, but abundant tumor-associated myeloid possibly explaining disappointing responses checkpoint blockade therapies cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, expression is absent malignant compartment gliomas, likely due methylation promoter. Nonetheless, several preclinical studies suggest inducing signaling could be beneficial, has been shown mediate inflammatory effects modalities either use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, oncolytic virotherapy. In this Review, we discuss its implications immunobiology, compartment-specific roles influencing surveillance, - directly indirectly antiglioma therapy.

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
Manganese-Enriched Zinc Peroxide Functional Nanoparticles for Potentiating Cancer Immunotherapy DOI
Mengli Zhou, Shuang Liang, Dan Liu

et al.

Nano Letters, Journal Year: 2023, Volume and Issue: 23(22), P. 10350 - 10359

Published: Nov. 6, 2023

Immunotherapies have shown high clinical success, however, the therapeutical efficacy is largely restrained by insufficient immune activation and an immunosuppressive microenvironment. Herein, we report tumor microenvironment (TME)-responsive manganese-enriched zinc peroxide nanoparticles (MONPs) for synergistic cancer immunotherapy inducing immunogenic death (ICD) of cells activating stimulator interferon gene (STING) pathway. MONPs especially disassociate upon exposure to acidic tissue in situ generate •OH ICD effect. Moreover, Mn2+ activated STING synergistically induced secretion type I inflammatory cytokines specific T cell responses. Meanwhile, relieved immunosuppression TME through decreasing Tregs polarizing M2 macrophages M1 unleash a cascade adaptive response. In combination with anti-PD-1 antibody, showed superior inhibiting growth preventing lung metastasis. Our study demonstrates feasibility functional amplify innate stimulation, showing prominent strategy immunotherapy.

Language: Английский

Citations

33
Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer DOI Open Access
Loretah Chibaya, Kelly D. DeMarco, Christina F. Lusi

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(762)

Published: Aug. 28, 2024

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in United States. This is part because its fibrotic tumor microenvironment (TME) that contributes poor vascularization and immune infiltration subsequent chemo- immunotherapy failure. Here, we investigated an approach combining delivery stimulator interferon genes (STING) Toll-like receptor 4 (TLR4) innate agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel suppressive PDAC TME through senescence-associated secretory phenotype. Treatment transplanted autochthonous mouse models these regimens led enhanced uptake NPs multiple cell types TME, induction type I other proinflammatory signaling pathways, increased antigen presentation cells antigen-presenting cells, activation both adaptive responses. two-pronged produced potent T cell–driven interferon–mediated regression long-term survival preclinical dependent on host STING activation. TLR4-mediated was also associated natural killer CD8 + immunity human samples. Thus, localized agonist systemic tumor-targeted therapy orchestrate a coordinated interferon–driven response durable antitumor efficacy against PDAC.

Language: Английский

Citations

13
5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation DOI Creative Commons
Burcu Temizoz, Takayuki Shibahara, Kou Hioki

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 12, 2024

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, reached phase III in lung cancer clinical trials. How effective against completely unknown. Here, we show that partial STING interfering with agonistic activation, which may explain its effect observed humans, as was reported to be pro-tumorigenic for cells low antigenicity. Furthermore, developed derivative—3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9 H -xanthen-9-one (HHMX)—that can potently antagonize STING-mediated immune responses both humans and mice. Notably, HHMX suppressed aberrant induced by gain-of-function mutations causing STING-associated vasculopathy onset infancy (SAVI) vitro experiments. treatment pathway activity peripheral blood mononuclear from SAVI patients. Lastly, showed potent therapeutic mouse model mitigating disease progression. Thus, offers potential autoinflammatory diseases.

Language: Английский

Citations

11
A Polymer-Based Antigen Carrier Activates Two Innate Immune Pathways for Adjuvant-Free Subunit Vaccines DOI

Hang Chen,

Luyao Wang, Xiao‐Fan Zhao

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(12), P. 9160 - 9175

Published: March 13, 2024

The activation of multiple Pattern Recognition Receptors (PRRs) has been demonstrated to trigger inflammatory responses and coordinate the host's adaptive immunity during pathogen infections. use PRR agonists as vaccine adjuvants reported synergistically induce specific humoral cellular immune responses. However, incorporating increases complexity design manufacturing. In this study, we discovered a polymer that can activate both Toll-like receptor (TLR) pathway cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) pathway. was then conjugated protein antigens, creating an antigen delivery system for subunit vaccines. Without additional adjuvants, antigen-polymer conjugates elicited strong antigen-specific Furthermore, conjugates, containing Receptor Binding Domain (RBD) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein or Monkeypox Antigen M1R were found potent antibodies, neutralizing cytotoxic T cells. Immunization with M1R-polymer also resulted in effective protection lethal challenge model. conclusion, platform offers effective, safe, simple strategy inducing against infectious diseases.

Language: Английский

Citations

11