Zheng Wang

Tumor innervation is increasingly recognized as an active component of the breast tumor microenvironment, where neural signals influence cancer cells, stromal populations, and immune responses through neurotransmitters, neuropeptides, and neurotrophic factors. Sympathetic, cholinergic, and sensory pathways can regulate tumor growth, migration, stromal remodeling, and immune activity, while neural signaling also intersects with tumor metabolism by modulating glycolysis, lipid mobilization, and amino acid utilization. Metabolic changes, including lactate accumulation and histone lactylation, may further reshape tumor and immune-cell states, linking neural activity with metabolic adaptation and immune regulation. These interactions vary across breast cancer subtypes, with adrenergic and sensory-neuropeptide signaling implicated in triple-negative breast cancer, metabolic adaptation during HER2-targeted therapy, and neurotrophic and adipose-tumor crosstalk in hormone receptor-positive/HER2-negative disease. We apply the recently proposed concept of the neuro–metabolic–immune axis to breast cancer, systematically evaluating the strength of evidence for each component and organizing the discussion by molecular subtype and therapeutic maturity. We further discuss therapeutic opportunities ranging from β-adrenergic and neuropeptide pathway modulation to downstream metabolic targeting, while distinguishing direct neural mechanisms from indirect or complementary evidence.

The adipocyte-rich microenvironment of the breast plays a crucial role in tumor progression, yet the functional heterogeneity of cancer-associated adipocyt

Angiogenesis, the formation of new blood vessels, is a pivotal process in breast cancer (BC) progression and metastasis, intricately regulated by complex interactions within the tumor microenvironment (TME). While the vascular endothelial growth factor (VEGF) pathway represents a cornerstone of these pro-angiogenic mechanisms, resistance to anti-VEGF therapies is common, underscoring the involvement of alternative pathways. Key insights reveal that hypoxia, metabolic reprogramming, and stromal components including cancer-associated fibroblasts (CAFs), cancer-associated adipocytes (CAAs) and immune cells, cooperate to drive aberrant angiogenesis and treatment resistance. This review synthesizes emerging evidence on the multifaceted regulation of angiogenesis by endothelial cells (ECs), pericytes, immune cells, and stromal components in shaping the angiogenic landscape, and discusses innovative therapeutic strategies. These include hypoxia-targeted agents, immune modulation, and combination therapies that co-target compensatory pathways. We emphasize that overcoming resistance requires integrated approaches that remodel the TME rather than solely inhibiting VEGF. Finally, we highlight ongoing clinical trials and translational opportunities aimed at improving outcomes and reducing metastasis in breast cancer patients.

Small extracellular vesicles (sEV) are a class of natural vesicles rich in heterogeneous cargos with the great advantage of non‐invasive detection; these vesicles exhibit complex intercellular crosstalk and mediate important biological functions. However, the potential value of plasma sEV in clinical prognosis prediction of triple‐negative breast cancer (TNBC) and their biological functions have not been well elucidated. In this study, we isolated sEV from non‐metastatic and metastatic TNBC plasma samples. We found that the expression of reticulin 4 (RTN4) in metastatic patients was significantly higher than that in non‐metastatic patients. At the same time, clinical data showed that RTN4 was associated with poor prognosis and advanced‐stage TNBC patients. Subsequently, in vivo and in vitro assays showed that compared to RTN4 ^Low sEV, RTN4 ^high sEV significantly promoted tumour cell migration, invasion, epithelial‐mesenchymal transition (EMT) and lung metastasis, and upregulated the expression of PD‐L1 in tumour tissues and inhibited CD8 ⁺ T cell infiltration. Regarding mechanism research, we found that RTN4 within sEV drives tumour EMT and PD‐L1 expression by activating the NF‐κB signalling pathway. Further, through the combined treatment experiment of anti‐PD‐1 and anti‐RTN4, it was found that the combination of the two drugs was significantly superior to monotherapy in inhibiting tumour metastasis, EMT, and promoting CD8 ⁺ T cell infiltration. Our results highlight the molecular mechanism of sEV protein RTN4 in tumour progression and immune system regulation, indicating that RTN4 targeting and anti‐PD‐1 combined therapy have clinical potential. sEV protein RTN4 is a potential new prognostic marker for non‐invasive detection of TNBC and a new target for TNBC treatment.

Metabolic reprogramming is a hallmark in cancer. Pyrimidine metabolism (PM), a part of nucleotide metabolism, has been shown to be associated with the progression of various cancers, and the prognostic predictive ability of pyrimidine metabolism-related genes (PMG) in breast cancer has not been elucidated. This paper was designed to identify pyrimidine metabolism-related prognostic marker of breast cancer and potential targeted therapeutic options. The cohort in the TCGA-BRCA dataset was used for patient information, and 108 pyrimidine metabolism-related genes were identified from the MSigDB KEGG pathways. We identified PM clusters in breast cancer and established a PM risk score model based on 10 pyrimidine metabolism-related genes. The status of immune infiltration was assessed in different groups. Further we identified the relevant hub gene and analyzed its significance for breast cancer metastasis and explored patterns of combination therapy. We identified three types of PM clusters in breast cancer and clarified that PM cluster C with inferior prognosis possessed activation of tumor proliferation-associated pathways. The high-risk group in PM risk score model was found to be characterized by an immunosuppressive microenvironment. The hub gene POLR2C (RNA polymerase II subunit C) was further identified and verified as a potential prognostic marker. Furthermore, targeting POLR2C in combination with anti-PD-1 and anti-angiogenic therapies demonstrated a promising tumor suppression effect, suggesting a potential therapeutic direction. These findings provide additional insights into the link between breast cancer and PMG, offering potential strategies for breast cancer management and treatment.

Introduction: Breast cancer is among the most prevalent malignant tumors globally, with carboplatin serving as a standard treatment option. However, resistance often compromises its efficacy. DNA damage repair (DDR) pathways are crucial in determining responses to treatment and are also associated with immune infiltration. This study aimed to identify the DDR genes involved in carboplatin resistance and to elucidate their effects on prognosis, immune infiltration, and drug sensitivity in breast cancer patients.Methods: A 3D-culture model resistant to carboplatin was constructed and sequenced. Co-expressed DDR genes were analyzed to develop a predictive model. Immune infiltration analysis tools were employed to assess the immune microenvironment of patients with varying expression levels of these risk genes. Additionally, drug sensitivity predictions were made to evaluate the efficacy of other DNA damage-related drugs across different risk groups. Molecular assays were performed to investigate the role of the key gene TONSL in breast cancer.Results: By integrating data from public database, we established a prognostic signature comprising thirteen DDR genes. Our analysis indicated that this model is associated with immune infiltration patterns in breast cancer patients, particularly concerning CD8+ T cells and NK cells. Additionally, it demonstrated a significant correlation with sensitivity to other DDR-related drugs, suggesting its potential as a biomarker for treatment efficacy. Compared to the control group, TONSL-knockdown cell lines exhibited a diminished response to DNA-damaging agents, marked by a notable increase in DNA damage levels and enhanced drug sensitivity. Furthermore, single-cell analysis revealed elevated TONSL expression in dendritic and epithelial cells, particularly in triple-negative breast cancers.Conclusions: Carboplatin resistance-related DDR genes are associated with prognosis, immune infiltration, and drug sensitivity in breast cancer patients. TONSL may serve as a potential therapeutic target for breast cancer, particularly in triple-negative breast cancer, indicating new treatment strategies for these patients.

Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC.

Breast cancer (BC) is a global health risk for women and has a high prevalence rate. The drug resistance, recurrence, and metastasis of BC affect patient prognosis, thus posing a challenge to scientists. Exosomes are extracellular vesicles (EVs) that originate from various cells; they have a double-layered lipid membrane structure and contain rich biological information. They mediate intercellular communication and have pivotal roles in tumor development, progression, and metastasis and drug resistance. Exosomes are important cell communication mediators in the tumor microenvironment (TME). Exosomes are utilized as diagnostic and prognostic biomarkers for estimating the treatment efficacy of BC and have the potential to function as tools to enable the targeted delivery of antitumor drugs. This review introduces recent progress in research on how exosomes influence tumor development and the TME. We also present the research progress on the application of exosomes as prognostic and diagnostic biomarkers and drug delivery tools.

Eleven two-carbon tethered artemisinin–isatin hybrids (4a–k) were designed, synthesized, and evaluated for their antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-231/ADR breast cancer cell lines, as well as cytotoxicity toward MCF-10A cells in this paper. Among them, the representative hybrid 4a (IC₅₀: 2.49–12.6 µM) was superior to artemisinin (IC₅₀: 72.4->100 µM), dihydroartemisinin (IC₅₀: 69.6–89.8 µM), and Adriamycin (IC₅₀: 4.46–>100 µM) against the three tested breast cancer cell lines. The structure–activity relationship revealed that the length of the alkyl linker between artemisinin and isatin was critical for the activity, so further structural modification could focus on evaluation of the linker. The in silico studies were used to investigate the mechanism of the most promising hybrid 4a. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid 4a may exert anti-breast cancer activity by acting on multiple targets such as EGFR, PIK3CA, and MAPK8 and thus participating in multiple tumor-related signaling pathways.

Breast cancer (BC) is one of the most prevalent malignancies and the major contributor to cancer mortality in women globally, with a high degree of heterogeneity and a dismal prognosis. As drug resistance is responsible for most BC fatalities and advanced BC is currently considered incurable, finding innovative anti‐BC chemotherapeutics is urgently required. Indole and its analog isatin (indole‐1H‐2,3‐dione) are prominent pharmacophores in the development of novel medications, and their derivatives exhibit strong anticancer activities, also against BC. In particular, indole/isatin hybrids exhibit significant potency against BC including multidrug‐resistant forms and excellent selectivity by influencing a variety of biological targets associated with the disease, supplying helpful building blocks for the identification of potential new BC treatment options. This review includes articles from 2020 to the present and provides insights into the in vitro and in vivo anti‐BC potential, molecular mechanisms, and structure–activity relationships (SARs) of indole/isatin hybrids that may be helpful in the development of innovative anti‐BC chemotherapeutics.