Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced‐Pulmonary Fibrosis

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

Published: May 7, 2024

Abstract Currently, the typical combination therapy of programmed death ligand‐1 (PD‐L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via upregulation some other checkpoint inhibitors. Apart from this, such may raise occurrence rate radiation‐induced lung fibrosis (RIPF) enhanced systemic inflammation, leading ultimate cancer patients (average survival time about 3 years). Therefore, it is newly revealed that mitochondria energy metabolism regulation can be used as a novel effective PD‐L1 transforming growth factor‐β (TGF‐β) dual‐downregulation method. Following IR‐TAM prepared by conjugating mitochondria‐targeted heptamethine cyanine dye IR‐68 oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self‐assembled albumin (Alb) form IR‐TAM@Alb nanoparticles. By doing tumor‐targeting nanoparticle effectively reversed tumor hypoxia depressed TGF‐β expression sensitize RT. Meanwhile, capacity targeting RIPF function TAM depressing TGF‐β, also ameliorated development induced

Language: Английский

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Supramolecular Lipid Nanoparticles Based on Host–Guest Recognition: A New Generation Delivery System of mRNA Vaccines For Cancer Immunotherapy

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(23)

Published: March 4, 2024

Abstract Dendritic cell (DC) maturation is a crucial process for antigen presentation and the initiation of T cell‐mediated immune responses. Toll‐like receptors play pivotal roles in stimulating DC promoting presentation. Here, novel message RNA (mRNA) cancer vaccine reported that boosts antitumor efficacy by codelivering an mRNA encoding tumor TLR7/8 agonist (R848) to using supramolecular lipid nanoparticles (SMLNP) as delivery platform, which new ionizable (N2‐3L) remarkably enhances translation efficiency β‐cyclodextrin (β‐CD)‐modified (Lip‐CD) encapsulates R848. The incorporation R848 adjuvant into through noncovalent host–guest complexation significantly promotes after vaccination, thus resulting superior vivo. Moreover, further boosted synergized with checkpoint blockade potentiating anticancer capability cytotoxic lymphocytes infiltrated sites. This work indicates SMLNP shows brilliant potential next‐generation system development vaccines high efficacy.

Language: Английский

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Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(3), P. e010612 - e010612

Published: March 1, 2025

Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated role tumor-cell-intrinsic function PD-L1 interleukin (IL)-6-mediated immunosuppression. Cohorts NSCLC treated and public datasets were analyzed. PD-L1-overexpressing PD-L1-knockdown cells submitted to RNA-seq, vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, biochemical assays. Human myeloid-derived suppressor (MDSCs) sorted peripheral blood mononuclear co-cultured then assessed for their immunosuppressive activity on T-cells. Mouse Lewis carcinoma (LLC) overexpression or knockdown subcutaneously injected into wild-type PD-1-knockout C57BL/6 mice presence IL-6 and/or PD-1 blockade. In cohort RNA-seq data, IL-6/Jak/Stat3 pathway was enriched, expression higher PD-L1-high NSCLCs who did not respond ICIs. another cohort, a baseline serum level associated poor clinical outcomes after therapy. enhanced cohorts The Cancer Genome Atlas analysis. correlated positively tumor-infiltrating MDSCs NSCLCs. cells, activated Jak2/Stat3 signaling by binding inhibiting protein tyrosine phosphatase 1B. also bound p-Stat3 nucleus, thus promoting transcription several cytokines (IL-6, TGF-β, TNF-α, IL-1β) chemokines. migration human vitro, mediated CXCL1. both mice, LLC tumors infiltrated increased high function, Tregs, decreased granzyme B+ IFNγ+ CD8 These responses secreted tumor cells. Combined blockade effective control while increasing drives immunosuppression progression through PD-L1/Jak/Stat3/IL-6/MDSC axis. This represents potential therapeutic target improve efficacy NSCLC.

Language: Английский

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Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy

Cancer Cell, Journal Year: 2025, Volume and Issue: 43(3), P. 503 - 518.e10

Published: March 1, 2025

Highlights•STING-induced PD-L1hi Tu.Mons dominate the resistance to STING agonist therapy•Cell-intrinsic PD-L1 induced by STING-IFN-I axis drives protumoral Tu.Mons•TLR2 activation rewires signaling reduce cell-intrinsic PD-L1•STING combined with TLR2 pre-activation shows enhanced antitumor efficacySummarySTING is an important DNA sensing machinery in initiating immune response, yet therapies targeting have shown poor outcomes clinical trials. Here, we reveal that induces tumor monocytes (Tu.Mons) against therapy. Cell-intrinsic PD-L1, STING-IRF3-IFN-I axis, identified as driving factor for Tu.Mons. Notably, TLR2-activated resist STING-induced upregulation of and associated functions. Mechanistically, stimulation remodels facilitating TRAF6 interaction, which suppresses IRF3-IFN-I response enhances NF-κB activation. Moreover, demonstrate combining agonists pretreatment significantly improves efficacy murine syngeneic humanized models. Our findings uncover a aspect mediated propose promising strategy boost immunity fine-tuning outputs.Graphical abstract

Language: Английский

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A Dual‐Locked Tandem Fluorescent Probe for Imaging of Pyroptosis in Cancer Chemo‐Immunotherapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 35(10)

Published: Nov. 1, 2022

Abstract Real‐time imaging of programmed cancer cell death (PCD) is imperative to monitor therapeutic efficacy and tailor regimens; however, specific in vivo detection intratumoral pyroptosis remains challenging. Herein, a dual‐locked tandem activatable probe (DTAP) reported for near‐infrared fluorescence (NIRF) during chemo‐immunotherapy living mice. The comprises hemicyanine dye with an enzyme‐responsive moiety that can be tandemly cleaved by pyroptosis‐related biomarker (Caspase‐1) (GGT) turn on its NIRF signal. As plays vital role triggering anti‐tumor immune responses, the activated signal DTAP correlates well population tumor‐infiltrating cytotoxic T lymphocytes tumor growth inhibition, consequently permitting prediction efficacy. This study also provides non‐invasive technique regulatory mechanism therapy optimize chemo‐immunotherapies precision medicine.

Language: Английский

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Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor–Induced Synthetic Lethality

Cancer Research, Journal Year: 2022, Volume and Issue: 82(11), P. 2156 - 2170

Published: March 3, 2022

BRCA1-mediated homologous recombination is an important DNA repair mechanism that the target of FDA-approved PARP inhibitors, yet details functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets cancer immunotherapies, but biological and mechanistic consequences their application incompletely understood. We show here molecule PD-L1 regulates in cells by promoting BRCA1 nuclear foci formation end resection. Genetic depletion tumor reduced recombination, increased nonhomologous joining, elicited synthetic lethality inhibitors olaparib talazoparib vitro some, not all, wild-type cells. In vivo, genetic rendered olaparib-resistant tumors sensitive olaparib. contrast, anti-PD-L1 blockade neither enhanced nor improved its efficacy or mice. Tumor did alter expression cofactor BARD1 instead coimmunoprecipitated with accumulation. CCL5 TANK-binding kinase 1 activation vitro, similar known immune-potentiating effects inhibitors. Collectively, these data define immune-dependent immune-independent inhibitor treatment depletion. Moreover, they implicate a cell-intrinsic, checkpoint-independent function cell damage translational potential, including as response biomarker.

Language: Английский

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Immune checkpoint receptors in autoimmunity

Current Opinion in Immunology, Journal Year: 2023, Volume and Issue: 80, P. 102283 - 102283

Published: Jan. 28, 2023

Language: Английский

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Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 73, P. 101037 - 101037

Published: Dec. 25, 2023

Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed co-occurrence CMA PD-L1 accumulation metastatic melanoma with adaptive immune resistance (AIR) anti-PD1 treatment, suggesting potential therapeutic effects rewiring degradation. Furthermore, attributed IFN-γ-mediated compensatory up-regulation CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from cellular uptake prions via macropinocytosis, prion-like chemical inducer proximity called SAP was engineered using self-assembly designed chiral peptide PHA. By exploiting sensitized clandestinely infiltrates tumor cells subsequently disintegrates into PHA, which reprograms inducing close HSPA8. degrades CMA-dependent manner effectively restores anti-tumor response both allografting Hu-PDX mouse models AIR while upholding high safety profile. Collectively, reported not only presents an reactivation strategy clinical translational overcoming cutaneous melanomas but serves as reproducible example precision-medicine-guided drug development that fully leverages specific indications pathological states.

Language: Английский

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Targeting inhibition of prognosis-related lipid metabolism genes including CYP19A1 enhances immunotherapeutic response in colon cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: April 13, 2023

Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed develop lipid metabolism-related prognostic risk score (LMrisk) provide new biomarkers combination therapy strategies for immunotherapy.Differentially expressed genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened construct LMrisk TCGA cohort. The was then validated three GEO datasets. differences of cell infiltration immunotherapy between subgroups investigated via bioinformatic analysis. These results comfirmed by vitro coculture cells peripheral blood mononuclear cells, human tissue microarray analysis, multiplex immunofluorescence staining mouse xenograft models cancer.Six LMGs CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 PPARGC1A selected establish the LMrisk. positively correlated abundance macrophages, carcinoma-associated fibroblasts (CAFs), endothelial levels immunotherapeutic programmed death ligand 1 (PD-L1) expression, mutation burden microsatellite instability, but negatively CD8+ T levels. CYP19A1 protein expression an independent factor, PD-L1 tissues. Multiplex analyses revealed that infiltration, tumor-associated CAFs cells. Importantly, inhibition downregulated PD-L1, IL-6 TGF-β through GPR30-AKT signaling, thereby enhancing cell-mediated antitumor co-culture studies. letrozole or siRNA strengthened anti-tumor induced normalization vessels, enhanced efficacy anti-PD-1 orthotopic subcutaneous models.A model based may predict prognosis cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality inhibits function upregulation signaling. combined PD-1 blockade represents promising therapeutic strategy

Language: Английский

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Targeted Drug Delivery Systems for Curcumin in Breast Cancer Therapy

International Journal of Nanomedicine, Journal Year: 2023, Volume and Issue: Volume 18, P. 4275 - 4311

Published: July 1, 2023

Abstract: Breast cancer (BC) is the most prevalent type of in world and main reason women die from cancer. Due to significant side effects conventional treatments such as chemotherapy radiotherapy, search for supplemental alternative natural drugs with lower toxicity interest researchers. Curcumin (CUR) a polyphenol extracted turmeric. Numerous studies have demonstrated that CUR an effective anticancer drug works by modifying different intracellular signaling pathways. CUR's therapeutic utility severely constrained its short half-life vivo, low water solubility, poor stability, quick metabolism, oral bioavailability, potential gastrointestinal discomfort high doses. One practical solutions aforementioned issues development targeted delivery systems (TDDSs) based on nanomaterials. To improve targeting efficacy serve reference use TDDSs clinical setting, this review describes physicochemical properties bioavailability mechanism action BC, emphasis recent BC combination CUR, including passive TDDSs, active TDDSs. Keywords: breast cancer, curcumin, system, targeting,

Language: Английский

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