Backgrounds: Hypoxia contributes to cancer progression, drug resistance and immune evasion in various cancers, including breast cancer (BC), but the molecular mechanisms have not been fully studied. Thus, the present study aimed to investigate this issue.Methods: The paclitaxel-sensitive BC (PS-BC) cells were administered with continuous low-dose paclitaxel treatment to establish paclitaxel-resistant BC (PR-BC) cells. Exosomes were isolated/purified by using the commercial kit, which were observed by Transmission electron microscopy (TEM). Cell viability was measured by MTT assay, cell apoptosis was determined by flow cytometer (FCM). Gene expressions were respectively measured by Real-Time qPCR, Western Blot and immunofluorescence staining assay. The peripheral mononuclear cells (PBMCs) derived CD8⁺ T cells were obtained and co-cultured with gp96-containing exosomes, and cell proliferation was evaluated by EdU assay. ELISA was employed to measure cytokine secretion in CD8⁺ T cells’ supernatants.Results: HSP gp96 was significantly upregulated in the cancer tissues and plasma exosomes collected from BC patients with paclitaxel-resistant properties. Also, continuous low-dose paclitaxel treatment increased gp96 levels in the descendent PR-BC cells and their exosomes, in contrast with the parental PS-BC cells. Upregulation of gp96 increased paclitaxel-resistance in PS-BC cells via degrading p53, while gp96 silence sensitized PR-BC cells to paclitaxel treatments. Moreover, PR-BC derived gp96 exosomes promoted paclitaxel-resistance in PS-BC cells and induced pyroptotic cell death in the CD8⁺ T cells isolated from human peripheral blood mononuclear cells (pPBMCs). Furthermore, we noticed that hypoxia promoted gp96 generation and secretion through upregulating hypoxia-inducible factor 1 (HIF-1), and hypoxia increased paclitaxel-resistance and accelerated epithelial-mesenchymal transition (EMT) in PS-BC cells.Conclusions: Hypoxia induced upregulation of intracellular and extracellular gp96, which further degraded p53 to increase paclitaxel-sensitivity in BC cells and activated cell pyroptosis in CD8⁺ T cells to impair immune surveillance.

Background: Breast cancer persists as a principal contributor to global cancer mortality, driven by heterogeneous molecular pathways. Necrosis by sodium overload, a recently characterized form of regulated cell death, remains underexplored in oncogenesis. This study investigates the pathobiological significance and therapeutic potential of NECSO-related genes in breast cancer, elucidating their mechanistic roles in tumor progression. Methods: Multi-omics analyses were performed using transcriptomic data from TCGA and GEO cohorts ( n = 1, 217), we systematically evaluated seven NECSO-related genes. Advanced bioinformatics pipelines included differential expression analysis, immune subtype profiling, functional state correlation, protein interaction mapping, and survival analytics. Experimental validation involved immunohistochemical evaluation of clinical samples. Results: Through multi-omics analysis of GEO and TCGA cohorts, we identified two sodium homeostasis-related genes, TRPM4 and SLC9A1, as consistently upregulated oncogenes in breast cancer, with significant diagnostic and prognostic relevance. Functional in vitro assays demonstrated that knockdown of either gene not only suppressed proliferation, colony formation, migration, and induced apoptosis in breast cancer cells, but also led to reduced expression of the sodium-calcium exchanger NCX1. Conclusion: TRPM4 and SLC9A1 is a novel prognostic biomarker and potential therapeutic target in breast cancer. Dysregulated sodium homeostasis mediated by NECSO-related genes represents a targetable vulnerability in precision oncology.

Triple‐negative breast cancer (TNBC) remains poorly responsive to immunotherapy, and how ferroptosis can be leveraged to enhance antitumor immunity is unclear. Here, we identify the mitochondrial aspartate/glutamate carrier SLC25A13 as a key immunometabolic driver in TNBC. SLC25A13 is upregulated in breast cancer, predicts poor prognosis, and is associated with reduced CD8 ⁺ T‐cell infiltration. Functionally, SLC25A13 promotes tumor growth, migration, and metastasis while suppressing ferroptosis and weakening CD8 ⁺ T‐cell‐mediated cytotoxicity. Mechanistically, SLC25A13 interacts with STAT3, enhances complex I‐linked oxidative phosphorylation, restrains mitochondrial ROS, and promotes STAT3 activation and nuclear translocation. Nuclear STAT3 directly induces IFI6, which preserves mitochondrial function, limits lipid peroxidation and Fe ^{2 +} accumulation, and thereby confers ferroptosis resistance and immune evasion. Through structure‐guided screening, we identified HY‐QS02682823 as a small‐molecule degrader of SLC25A13 that triggers lysosome‐dependent SLC25A13 loss, enhances ferroptosis, restores CD8 ⁺ T‐cell effector function, and improves the efficacy of anti‐PD‐1 therapy in syngeneic TNBC models. These findings identify the SLC25A13–STAT3–IFI6 axis as a key regulator of ferroptosis resistance and immune evasion in TNBC.

Invasive micropapillary carcinoma (IMPC) is a rare breast cancer subtype with high invasiveness and lymphovascular/lymph node metastasis. While poor prognosis is reported, long-term survival and roles of molecular subtyping/laboratory markers remain unclear. We retrospectively analyzed 653 IMPC patients from a Chinese center (as of December 2024). Kaplan-Meier estimated progression-free survival (PFS) and overall survival (OS); Cox regression assessed prognostic factors. Among 653 patients with IMPC, the molecular subtype distribution was as follows: HR+/HER2−, 48.2%; HR+/HER2+, 35.4%; HR−/HER2−, 11.0%; and HR−/HER2+, 5.4%. Most patients had T1–2 disease and were postmenopausal. The 3-year and 5-year OS rates were 97.42% and 93.73%, respectively, while the 3-year and 5-year PFS rates were 90.66% and 81.20%, respectively. Kaplan–Meier analysis showed significant differences in PFS among molecular subtypes, but not in OS. In multivariable analysis, the HR+/HER2+ subtype and higher total bilirubin were independently associated with better PFS, whereas higher systemic immune-inflammation index and stage IIIB were associated with worse PFS. Poorer OS was independently associated with advanced stage, no surgery, alcohol consumption history, higher systemic immune-inflammation index, menopausal status, and elevated blood glucose, while mastectomy and endocrine therapy were associated with better OS. IMPC shows favorable OS but requires progression risk monitoring. PFS varied by molecular subtype, while OS did not. Molecular typing, clinical stage, and inflammatory/biochemical markers aid prognosis and personalized treatment.

Breast cancer is generally characterized by limited immunogenicity. Although immune checkpoint inhibitors (ICIs) provide survival benefits in a subset of patients with triple-negative breast cancer (TNBC), overall response rates remain limited and are accompanied by pronounced therapeutic heterogeneity and systemic immune-related adverse events. The immunosuppressive tumor immune microenvironment (TIME), characterized by restricted antigen presentation, limited effector T-cell infiltration, and enrichment of immunosuppressive cell populations, represents a key barrier to durable immunotherapy benefit. Dissolving microneedles (DMNs) represent a minimally invasive transdermal delivery system that bypasses the stratum corneum barrier. They enable the delivery of antigens and immunomodulatory molecules into the epidermis and superficial dermis enriched in antigen-presenting cells (APCs), thereby facilitating efficient peripheral immune priming while reducing systemic exposure. This review summarizes the material composition and microstructural design of DMNs, their transdermal immunodelivery characteristics, and recent advances in breast cancer immunotherapy. It further highlights the mechanisms by which DMNs mediate peripheral immune activation and remodel the TIME, as well as their potential in combination with other immunotherapeutic strategies. Overall, DMNs represent a promising strategy that may improve the efficacy and safety of breast cancer immunotherapy by enabling localized delivery, efficient peripheral activation, and coordinated microenvironment remodeling.