Biodegradable nanofibrous drug-eluting seed for sustained intratumoral immunotherapy.

Vascular disruption-triggered physiological cascade enables a therapeutic window for fibrin-hypoxia dual-targeting nanomedicines in solid tumors.

Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3), a key deubiquitinating enzyme of the UCH family, has been implicated in DNA repair in breast cancer; however, its role in regulating cell migration and invasion in triple-negative breast cancer (TNBC) remains poorly understood. The expression pattern of UCHL3 across breast cancer subtypes was analyzed using TCGA data. In TNBC cells, UCHL3 mRNA levels were quantified by qRT-PCR, while its protein expression and epithelial-mesenchymal transition (EMT) markers (Vimentin, N-cadherin, SNAIL, E-cadherin, α-SMA, TWIST) were assessed by Western blot. Functional assays included: MTT and EdU incorporation assays for proliferation; wound healing and Transwell migration assays for migratory capacity. Transcriptomic changes induced by UCHL3 knockdown were profiled via RNA sequencing. Additionally, an in vivo mice model was used to evaluate the pro-invasive effects of UCHL3 overexpression in TNBC. UCHL3 was significantly overexpressed in TNBC and correlated with poor patient prognosis. Functional studies revealed that UCHL3 enhances the proliferative capacity of TNBC cells. Furthermore, UCHL3 was demonstrated to promote TNBC cell migration and invasion through modulation of epithelial-mesenchymal transition (EMT) markers. Mechanistically, knockdown of UCHL3 attenuated activation of invasion- and migration-related signaling pathways in TNBC cells. Pharmacological inhibition of UCHL3 effectively suppressed TNBC cell migration and invasion in vitro. In vivo studies further confirmed that UCHL3 overexpression drives metastatic progression of TNBC in mice. UCHL3 is significantly upregulated in TNBC and drives tumor progression by promoting cell proliferation and activating EMT-mediated migration and invasion. These findings identify UCHL3 as a potential therapeutic target for TNBC treatment.

The 2021 American Society of Clinical Oncology (ASCO) guidelines recommend neoadjuvant systemic therapy (NST) over upfront surgery for human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancers if node-positive or at least T1c. In practice, many clinicians use a 2-cm (T2) or node-positive threshold for NST, leaving controversy regarding management of clinically node-negative T1c HER2+ and triple-negative tumors. Accurate estimation of nodal status is therefore essential to guide management. This study evaluated the association between tumor size and nodal involvement in T1-T2 HER2+ and triple-negative tumors and assessed predictors of nodal positivity in T1c tumors. A population-based retrospective cohort study was conducted using Institute for Clinical Evaluative Sciences (ICES) Ontario administrative data (2000-2019). The primary outcome was regional nodal positivity (N1-N3) stratified by tumor size (T1a-T2) and receptor subtype. Multivariable logistic regression identified independent predictors of nodal positivity in T1c tumors. The study analyzed 11,007 T1a-T2 cases including 1923 hormone receptor-negative (HR-)-HER2+ cases, 4542 HR+HER2+ cases, and 4542 triple-negative cases. Among T1a/b tumors, the nodal positivity rates ranged from 11 to 22% for HR-HER2+, 11-14% for HR+HER2+, and 7-11% for triple-negative tumors. Among T1c tumors, the rates were 32% for HR-HER2+, 26% for HR+HER2+, and 19% for triple-negative tumors. Among T2 tumors, the rates were 38% for HR-HER2+, 42% for HR+HER2+, and 30% for triple-negative tumors. Among T1c tumors, HR-HER2+ subtype and patient age younger than 50 years were independently associated with increased odds of nodal positivity. Nodal positivity rates are substantial for T1-T2 HER2+ and triple-negative tumors, even for T1a/b tumors. Among T1c tumors, HR-HER2+ subtype and age of 50 years or younger independently predicted increased nodal positivity, supporting NST especially for these patients.

The identification of novel therapeutic targets and agents to overcome chemoresistance remains a central challenge in triple-negative breast cancer (TNBC). Here, we report three key innovations: the discovery of a novel oncogenic circRNA, circPARPBP, as a driver of chemoresistance; the elucidation of its mechanism through the recruitment of the SRCAP complex to activate CCL20 transcription and cancer stemness; and the demonstration that the natural compound isoliquiritigenin (ISL) effectively suppresses this axis to overcome chemoresistance. TNBC is the most aggressive subtype of breast cancer with poor prognosis and limited treatment options. In this study, we identified circPARPBP, a circRNA (hsa_circ_0000432) derived from PARPBP gene, which was aberrantly upregulated in TNBC tissues and cells. Clinically, the upregulation of circPARPBP was notably associated with TNBC chemoresistance. In vitro and in vivo experiments demonstrated that circPARPBP promoted TNBC progression and chemoresistance. Mechanistically, circPARPBP recruited the SNF2-related CBP activator protein (SRCAP) complex to activate C-C motif chemokine ligand 20 (CCL20) transcription and thus contributed to cancer stemness and chemoresistance. ISL, a key bioactive substance extracted from licorice root, effectively suppressed the circPARPBP-SRCAP-CCL20 signaling pathway. Notably, patient-derived xenograft models demonstrated that ISL treatment effectively overcame TNBC chemoresistance, with a superior benefit when in combination with conventional chemotherapy. Collectively, our study identifies circPARPBP as a novel regulator of TNBC progression and chemoresistance via SRCAP-mediated CCL20 activation, and provides a preclinical rationale for the clinical development of ISL as a potential therapy targeting this axis.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and currently lacks defined therapeutic targets. Although miR-152-3p functions as a tumor suppressor in various cancers, its specific mechanism and regulatory network in TNBC remain poorly understood. To investigate the expression and tumor-suppressive function of miR-152-3p in TNBC cells and to elucidate its mechanism of targeting STAT3, RELA and ADCY6. miR-152-3p expression was compared between MDA-MB-231 and MCF-10A cells using qRT-PCR. MDA-MB-231 cells were transfected with miR-152-3p mimics or inhibitors and cell proliferation, apoptosis and invasion were assessed by MTT assay, flow cytometry and Transwell assay, respectively. Direct target interactions were validated by a dual-luciferase reporter assay, and protein levels of STAT3, RELA, and ADCY6 were examined by Western blot. Key findings were further validated in Hs 578T cells. miR-152-3p expression was significantly downregulated in TNBC cells. Overexpression of miR-152-3p markedly inhibited proliferation and invasion while promoting apoptosis in MDA-MB-231 cells. Dual-luciferase reporter assays confirmed that miR-152-3p directly binds to the 3'untranslated regions of STAT3, RELA and ADCY6. Overexpression of miR-152-3p significantly reduced STAT3 and RELA protein levels while upregulating ADCY6 expression. Rescue experiments demonstrated that restoration of STAT3 expression partially reversed the tumor-suppressive effects of miR-152-3p. These findings were recapitulated in Hs 578T cells, suggesting generalizability across TNBC subtypes. miR-152-3p suppresses TNBC progression by downregulating STAT3/RELA and upregulating ADCY6, thereby activating cAMP signaling. These findings provide a foundation for further investigation into the potential of miR-152-3p as a multi-target therapeutic strategy for TNBC.

Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined. We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response. We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype-compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g. HR = 4.7, P = 0.01) and TLR7score-low (HR = 3.37, P = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell-related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner. Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.

PMEPA1 promotes mTOR inhibitor resistance in triple-negative breast cancer: Targeting the TGF-β/PMEPA1 axis as a therapeutic strategy to overcome resistance.

FLASH radiotherapy induces unique immunotranscriptomic profiles compared to conventional dose-rate radiotherapy, despite identical immune infiltration and antitumor efficacy in a murine model of triple-negative breast cancer.

Immune checkpoint blockade, exemplified by anti-PD-L1 antibody (αPD-L1), has revolutionized cancer immunotherapy. Nevertheless, its therapeutic potential is constrained by the inherently low tumor immunogenicity and the persistence of cancer stem cells (CSCs), which drive immune escape and tumor recurrence. Here, a CSC-targeted, pH-sensitive liposomal nano-cocktail of doxorubicin and bufalin (PSLB/D), was demonstrated to elicit robust immunogenic cell death (ICD), thereby potentiating the efficacy of αPD-L1 in immunologically 'cold' triple-negative breast cancer (TNBC) models. The PSLB/D itself demonstrated potent synergistic tumor-inhibitory effects in both cell lines and 3-D tumor spheroids, and effectively eliminated CSCs, with 85-90% reductions in both primary and secondary sphere formation. Deep penetration and robust ICD-mediated immune response were observed in patient-derived organoids, highlighting its translational potential. The therapeutic efficacy was validated in immunocompromised MDA-MB-231 and immunocompetent 4T1 orthotopic mouse models. Notably, in immunocompetent 4T1 models, PSLB/D induced strong expression of calreticulin, leading to the recruitment of dendritic cells and cytotoxic CD8⁺ T cells. Activation of these immune cells converted the immunosuppressive 'cold' tumors into immunogenic 'hot' ones, substantially amplifying the effectiveness of αPD-L1. This chemo-immunotherapy also generated memory T cells, suggesting the potential for longer antitumor immune responses. STATEMENT OF SIGNIFICANCE: Cancer recurrence and immune evasion in triple-negative breast cancer (TNBC) are largely driven by resilient cancer stem cells (CSCs). This study introduces a pH-sensitive liposomal nano-cocktail composed of doxorubicin and a CSC inhibitor, specifically engineered to overcome the immunosuppressive tumor microenvironment. We demonstrate that this nanococktail triggers potent immunogenic cell death (ICD) in patient-derived organoids and orthotopic models, exceeding the efficacy of conventional formulations or monotherapy. By successfully converting "cold" TNBC tumors into immunologically "hot", the nano-cocktail significantly amplifies anti-PD-L1 immunotherapy outcomes. These findings offer a compelling evidence-based framework for integrating targeted nanomedicine with clinical chemo-immunotherapy protocols to prevent recurrence.

Epidermal growth factor receptor (EGFR) is overexpressed in most triple-negative breast cancer (TNBC) patients with poor prognosis; however, the therapeutic benefit of EGFR inhibitors (EGFRi) in breast cancer remains limited. In this study, we found poor response to EGFRi in TNBC was related to oxidative phosphorylation (OXPHOS) and breast cancer stem cells (BCSCs), and demonstrated that TDP43 (TAR DNA-binding protein 43) expression is positively correlated with non-response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). TDP43 knockdown significantly enhances EGFR-TKI sensitivity and decreases EGFR-TKI resistance. Mechanistically, TDP43, a DNA/RNA-binding protein predominantly localized to the nucleus, translocates to mitochondria upon EGFR-TKI stimulation. The increased mitochondrial localization promotes OXPHOS, thereby enriching BCSCs and contributing to EGFR-TKI resistance. Inhibiting TDP43 expression or using our newly identified TDP43 inhibitor, atovaquone, suppresses OXPHOS and reduces EGFR-TKI resistance. Overall, our research identified TDP43 as a key regulator of EGFR-TKI sensitivity and resistance, and offers new therapeutic targets and promising application perspectives in TNBC.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, with limited treatment options. Tumor-associated macrophages (TAMs), as key immune cells in the tumor microenvironment, exacerbate the malignancy of TNBC by promoting angiogenesis, metastasis, immune evasion, and drug resistance. We systematically searched PubMed, Web of Science, and ClinicalTrials.gov databases to collect clinical trials targeting TAMs for the treatment of TNBC. Data from completed and ongoing studies were extracted and analyzed, focusing on strategies that inhibit macrophage recruitment, clearance, and reprogramming, as well as their combination with standard therapies. TAMs in TNBC predominantly exhibit an M2-like pro-tumor phenotype, originating from circulating monocytes and tissue-resident macrophages, and drive progression through multiple pathways. Clinical trials indicate preliminary efficacy for strategies including CSF-1/CSF-1R inhibitors, bisphosphonates, and reprogramming agents-particularly when combined with chemotherapy or immune checkpoint inhibitors-though response rates vary, and optimal regimens remain under investigation. TAMs represent a promising therapeutic target in TNBC. Emerging clinical evidence supports the potential of targeted therapies against them, though further optimization of patient selection and combination strategies is required. This review provides a systematic foundation for advancing treatments targeting TAMs. We confirm that the scientific content remains unchanged.

Biomimetic cascade "four-in-one" Nanozyme for remodeling the redox tumor microenvironment and disrupting energy homeostasis to enhance ferroptosis against triple-negative breast cancer.

Engineering biodegradable lipid nanoparticles with endo-lysosomal escape capability for chronological therapeutic immunomodulation to enhance interleukin-15 therapy.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, known for its high malignancy, elevated risk of recurrence and metastasis, and limited therapeutic options, resulting in the poorest prognosis among breast cancer types. This study explores the anticancer effects of VALD-3, a Schiff base ligand derivative, on breast cancer cells. While VALD-3 exhibited cytotoxic effects on both triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER+) MCF-7 cells, it more potently inhibited TNBC cell viability. More importantly, VALD-3 induced characteristic pyroptotic features selectively in TNBC cells, including cell swelling, balloon-like protrusions, and the release of inflammatory cytokines due to pore formation in the plasma membrane, ultimately inhibiting tumor growth. Mechanistically, VALD-3 increased reactive oxygen species (ROS) levels and JNK phosphorylation, leading to the recruitment of Bax to the mitochondria and the formation of a Bax-Bcl-2 heterodimer, which facilitated cytochrome c release into the cytoplasm. This cascade activated caspase-3 and triggered gasdermin E(GSDME)- dependent pyroptosis in TNBC cells. Thus, VALD-3 treatment initiated the ROS/JNK/Bax-mitochondrial apoptosis pathway, leading to caspase-3 activation and GSDME cleavage, thereby executing pyroptosis. These findings suggest that GSDME-dependent pyroptosis is a novel mechanism by which VALD-3 eradicates cancer cells and offer new insights into potential clinical applications for anticancer therapies.

ALK protein expression and gene copy number alterations in triple-negative breast cancer: Clinical implications.

Silver-selenium hybrid nanocomposite with combined cytotoxic and metabolic reprogramming effects in triple-negative breast cancer.

Urea-based lysophosphatidic acid receptor 1 antagonists as potential migrastatics for triple-negative breast cancer.

Targeting mitochondria in triple-negative breast cancer: Emerging therapeutic and drug development strategies.

Genetically engineered cellular membrane-camouflaged nanoparticles amplify immune response against recurrent metastatic triple-negative breast cancer.