Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers

Drug Resistance Updates, Год журнала: 2024, Номер 73, С. 101042 - 101042

Опубликована: Янв. 4, 2024

Drug resistance in cancer remains a major challenge oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as critical player development drug cells. This comprehensive review explores intricate relationship between NF-κB and cancer. We delve into molecular mechanisms through which activation contributes to against chemotherapeutic agents, targeted therapies, immunotherapies. Additionally, we discuss potential strategies overcome this by targeting signaling, such small molecule inhibitors combination therapies. Understanding multifaceted interactions is crucial for more effective strategies. By dissecting complex network NF-κB, hope shed light on novel therapeutic approaches that can enhance outcomes, ultimately improving prognosis patients. aims provide overview current state knowledge its role resistance, offering insights may guide future research interventions fight

Язык: Английский

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Targeting triple negative breast cancer stem cells using nanocarriers

Discover Nano, Год журнала: 2024, Номер 19(1)

Опубликована: Март 7, 2024

Abstract Breast cancer is a complex and heterogeneous disease, encompassing various subtypes characterized by distinct molecular features, clinical behaviors, treatment responses. Categorization of based on the presence or absence estrogen receptor (ER), progesterone (PR), human epidermal growth factor 2 (HER2), leading to such as luminal A, B, HER2-positive, triple-negative breast (TNBC). TNBC, comprising around 20% all cancers, lacks expression ER, PR, HER2 receptors, rendering it unresponsive targeted therapies presenting significant challenges in treatment. TNBC associated with aggressive behavior, high rates recurrence, resistance chemotherapy. Tumor initiation, progression, are attributed stem cells (BCSCs), which possess self-renewal, differentiation, tumorigenic potential. Surface markers, self-renewal pathways (Notch, Wnt, Hedgehog signaling), apoptotic protein (Bcl-2), angiogenesis inhibition (VEGF inhibitors), immune modulation (cytokines, checkpoint inhibitors) among key targets discussed this review. However, targeting BCSC subpopulation presents challenges, including off-target effects, low solubility, bioavailability anti-BCSC agents. Nanoparticle-based offer promising approach target cellular processes implicated survival BSCS TNBC. In review, we explore nanocarrier-based approaches for BCSCs aiming overcome these improve outcomes patients. These nanoparticle-based therapeutic strategies hold promise addressing gap delivering while minimizing systemic toxicity enhancing efficacy. Graphical abstract

Язык: Английский

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Platycodon grandiflorum-derived extracellular vesicles suppress triple-negative breast cancer growth by reversing the immunosuppressive tumor microenvironment and modulating the gut microbiota

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Фев. 7, 2025

Despite the approval of several artificial nanotherapeutics for treatment triple-negative breast cancer (TNBC), significant challenges, including unsatisfactory therapeutic outcomes, severe side effects, and high cost large-scale production, still restrict their long-term application. In contrast, plant-derived extracellular vesicles (PEVs) exhibit promising potential in therapy due to negligible systemic toxicity, bioavailability cost- effectiveness. this study, we developed an alternative strategy inhibit TNBC via Platycodon grandiflorum (PG)-derived (PGEVs). The PGEVs were isolated by ultracentrifugation sucrose gradient centrifugation method contained adequate functional components such as proteins, lipids, RNAs active molecules. exhibited remarkable stability, tolerating acidic digestion undergoing minimal changes simulated gastrointestinal fluid. They efficiently taken up tumor cells induced increased production reactive oxygen species (ROS), leading cell proliferation inhibition apoptosis, particularly line 4T1. Additionally, facilitated polarization tumor-associated macrophages (TAMs) toward M1 phenotype secretion pro-inflammatory cytokines. Further vivo investigations revealed that accumulated 4T1 tumors exerted effects through boosting anti-tumor immune responses modulating gut microbiota whether administered orally or intravenously (i.v.). conclusion, these findings highlight a natural, biocompatible efficient nanotherapeutic candidate treating TNBC.

Язык: Английский

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Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 2, 2023

Abstract Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates the targeted delivery glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels immunosuppressive TME enhance response. Poly β-amino ester (PAE)-modified CTLA-4-antagonizing aptamers (aptPD-L1 aptCTLA-4) synthesized co-assembled into supramolecular nanoassemblies carrying BAY-876. The acidic microenvironment causes PAE protonation triggers dissociation initiate aptamer release. selectively inhibits glycolysis deprive uridine diphosphate N-acetylglucosamine downregulate N-linked glycosylation, thus facilitating recognition aptPD-L1 anti-PD-L1 therapy. Meanwhile, treatment also elevates supply tumor-residing cells (Tregs) metabolically rewiring them an immunostimulatory state, cooperating with aptCTLA-4-mediated immune-checkpoint inhibition abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms in preclinical models female mice provides distinct approach immunotherapy clinics.

Язык: Английский

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Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment

Pharmacological Research, Год журнала: 2024, Номер 204, С. 107205 - 107205

Опубликована: Май 6, 2024

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, imbalances in regulators such as BET proteins, plays a crucial role development resistance to treatment. Hypermethylation tumor suppressor gene promoters the imbalance methyltransferases EZH2 deacetylases (HDACs) profoundly influence cell proliferation, survival, metastasis. In addition, epigenetic alterations critically shape microenvironment (TME), composition, cytokine signaling, expression, ultimately contributing evasion. Targeting these mechanisms with specific inhibitors HDAC combination immunotherapy represents compelling strategy remodel TME, potentially overcoming evasion enhancing therapeutic outcomes TNBC. review aims comprehensively elucidate current understanding modulation TNBC, on potential combining therapies overcome posed by this subtype.

Язык: Английский

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The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 12, 2024

Abstract Objective The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of checkpoints progression triple-negative breast (TNBC). Methods We evaluated CD155 and TIGIT expression TNBC tissues using both immunohistochemistry (IHC) gene profiling. experiments, vivo vitro, provided evidence that inhibiting pathway reinstates ability CD8 + T cells to generate cytokines. To assess impact signaling blockade, we utilized Glucose Assay Kits Lactate measure alterations glucose lactate levels within cells. employed western blotting (WB) investigate glycolytic-related proteins PI3K/AKT/mTOR pathways following inhibition signaling. Results exhibits heightened a negative correlation extent infiltrating Furthermore, patients demonstrate elevated expression. findings indicate interaction between disrupts metabolism by suppressing activation pathway, ultimately leading reduced production cytokines Both vitro experiments have conclusively demonstrated capacity Moreover, administration blocking antibody against not only inhibits tumor growth but also augments functionality lymphocytes. Conclusions strongly suggest represents promising therapeutic target for treating TNBC.

Язык: Английский

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Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions

Cancer Letters, Год журнала: 2024, Номер 590, С. 216856 - 216856

Опубликована: Апрель 5, 2024

Язык: Английский

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Association of tumor-infiltrating lymphocytes with clinical outcomes in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a systematic review and meta-analysis

Clinical & Translational Oncology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 18, 2024

Язык: Английский

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Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

Biomedicines, Год журнала: 2024, Номер 12(2), С. 369 - 369

Опубликована: Фев. 5, 2024

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with pronounced immunogenicity, exhibiting rapid proliferation and immune cell infiltration into the tumor microenvironment. TNBC’s heterogeneity poses challenges to immunological treatments, inducing resistance mechanisms in Therapeutic modalities, including checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, CTLA-4, are explored preclinical clinical trials. Promising results emerge from combining ICIs anti-TGF-β VISTA, hindering TNBC growth. cells employ complex evasion strategies involving interactions stromal cells, suppressing recognition through various cytokines, chemokines, metabolites. The recent focus on unraveling humoral cellular components aims disrupt crosstalk within This review identifies latest mechanisms, exploring potential targets for trials overcome enhance patient survival rates.

Язык: Английский

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Toll-like receptors in breast cancer immunity and immunotherapy

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 6, 2024

Toll-like receptors (TLRs) are a key family of pattern recognition (PRRs) in the innate immune system. The activation TLRs will not only prevent pathogen infection but also respond to damage-induced danger signaling. Increasing evidence suggests that play critical role breast cancer development and treatment. However, is double-edged sword can induce either pro-tumor activity or anti-tumor effect. underlying mechanisms these opposite effects TLR signaling fully understood. Targeting promising strategy for improving treatment, as monotherapies by other current therapies. Here we provide an update on immunity immunotherapy.

Язык: Английский

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