Background Spermidine (SPD) dysregulation is common in multiple cancers and is associated with reduced survival of cervical cancer (CC) cells. However, the mechanisms underlying SPD's role in CC progression remain poorly understood. This study aimed to investigate how SPD metabolism influences ferroptosis in cervical cancer. Methods Using bioinformatics analysis of public databases and immunohistochemistry on clinical specimens, we assessed the expression of SPD metabolic enzymes. In vitro experiments were conducted using HeLa and SiHa cervical cancer cell lines. Cell viability was measured by CCK-8 assay, mitochondrial morphology was observed via transmission electron microscopy, and protein expression was analyzed by Western blot. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were quantified using fluorescent probes and biochemical assays. Statistical significance was determined using Student’s t-test or one-way ANOVA. Results We identified elevated expression of the rate-limiting SPD metabolic enzyme SAT1 in cervical cancer tissues. SPD treatment induced ferroptosis in CC cells, as demonstrated by decreased Glutathione Peroxidase 4 (GPX4) expression, increased ROS and MDA levels, and characteristic mitochondrial alterations. Overexpression of SAT1 or supplementation with its downstream metabolite N 1 -acetylspermidine enhanced ferroptosis. Importantly, both SPD and N 1 -acetylspermidine attenuated the ferroptosis resistance caused by SAT1 inhibition. Conclusion Our findings reveal that enhanced SAT1-mediated SPD metabolism promotes ferroptosis in cervical cancer, suggesting that targeting this metabolic pathway could represent a novel therapeutic strategy for CC treatment.

Rationale:Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its 'cold' immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered 'disarm-and-attack' cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment. Methods:Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated in vitro using 4T1 cells. In vivo anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade. Results:The platform first releases H2S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu2+ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn2+ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and in vivo experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8+ T cell infiltration and enhanced dendritic cell maturation. Conclusion:Combining this nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.

Background The potential association between micro-/nanoplastics and cancer has raised increasing concerns. However, research focusing specifically on breast cancer (BC), and particularly on triple-negative breast cancer (TNBC), remains limited, leading to a critical gap in current knowledge. This study seeks to explore potential correlative effects of micro-/nanoplastic exposure on TNBC progression. Methods We employed scanning electron microscopy, micro-Raman spectroscopy, and pyrolysis–gas chromatography-mass spectrometry to characterize micro-/nanoplastics in BC tissues. Moreover, spatial transcriptomics (ST) analysis was applied to characterize putative molecular changes associated with polyethylene terephthalate (PET) micro-/nanoplastic exposure and TNBC progression, followed by in vitro and in vivo assays to further investigate these changes. Results A variety of micro-/nanoplastics were detected in human BC tissues. Among them, based on the results of the ST analysis, PET might be related to the downregulation of spermine/spermidine N1-acetyltransferase 1 (SAT1) in TNBC tumor cells and the inhibition of ferroptosis. Moreover, in vitro and in vivo data showed that, following PET treatment, SAT1 expression and ferroptosis were significantly downregulated, whereas TNBC cell proliferation and xenograft growth were significantly upregulated. Additionally, in vitro experiments further suggested that PET micro-/nanoplastics could interact with BC cells via particle endocytosis or surface adsorption. Conclusions This study suggests that SAT1-dependent ferroptosis may be a potential molecular pathway that links PET micro/nanoplastic exposure to TNBC progression. This finding provides novel insights into the possible toxicological association between micro-/nanoplastic exposure and TNBC progression.

Gallbladder cancer (GBC) is a highly aggressive malignancy with a poor response to immune checkpoint blockade (ICB), highlighting an urgent need to understand the mechanisms of immune evasion. We identified the orphan nuclear receptor ERRα as a critical regulator of the immunosuppressive tumor microenvironment in GBC. Mechanistically, we discovered that ERRα transcriptionally upregulates the ETS-family transcription factor ETV5, which in turn directly binds to and activates the PD-L1 (CD274) promoter, establishing a novel ERRα-ETV5-PD-L1 signaling axis.​ In clinical specimens, ERRα expression positively correlated with PD-L1 levels and served as an independent prognostic factor for poor survival. Using a combination of human GBC tissues, in vitro co-culture systems, and a humanized mouse model, we demonstrated that genetic or pharmacological inhibition of ERRα downregulated PD-L1 and potentiated CD8+ T cell-mediated cytotoxicity.​ Critically, combined targeting of ERRα (using the inverse agonist XCT790) and PD-L1 (using durvalumab) synergistically suppressed tumor growth and enhanced intratumoral T cell infiltration in vivo. Our findings reveal ERRα as a master transcriptional regulator of immune evasion and highlight the therapeutic potential of co-inhibiting the ERRα-ETV5-PD-L1 axis to overcome immunotherapy resistance in GBC.

ObjectivesTo examine the associations of maternal vitamin D (VitD) concentrations in early- and mid-pregnancy with offspring growth trajectories from birth to 6 years of age, as well as childhood overweight.MethodsThis study was a prospective observational cohort study including 1,100 mother–child dyads from the Wuxi Birth Cohort. Offspring weight-, height-, and BMI-for-age Z-scores (WAZ, HAZ, and BAZ) were collected from birth to 6 years of age. Growth trajectories were identified using group-based trajectory modeling (GBTM). Restricted cubic spline (RCS) analyses explored the nonlinear associations. Multivariable logistic regression was used to assess associations of maternal VitD tertiles (T1-T3) with growth trajectory groups and overweight risk, with exploratory analyses stratified by child sex.ResultsLower early pregnancy VitD concentrations (T1 vs. T2) were associated with higher odds of increasing HAZ (aOR, 1.84; 95% CI, 1.16, 2.92) and BAZ (aOR, 1.63; 95% CI, 1.09, 2.43) trajectories. Lower mid-pregnancy VitD concentrations were associated with higher odds of increasing WAZ (aOR, 3.21; 95% CI, 1.41, 7.34) and HAZ (aOR, 1.94; 95% CI, 1.03, 3.66) trajectories. Higher early pregnancy VitD concentrations (T3 vs. T2) were associated with higher odds of increasing BAZ, particularly among boys (aOR, 2.11; 95% CI, 1.16, 3.82). Sex-stratified analyses suggested stronger associations for WAZ- and BAZ-related trajectories in boys and HAZ-related trajectories in girls. RCS analyses showed nonlinear associations, with the lowest odds of adverse trajectories observed at 27.6–72.6 nmol/L in early pregnancy and 28.8–76.2 nmol/L in mid-pregnancy. Overweight at age 6 was nearly ten times more common in children with increasing vs. stable BAZ trajectories.ConclusionMaternal VitD levels in early- and mid-pregnancy showed nonlinear and sex-specific associations with offspring growth trajectories. Both low and high maternal VitD levels during these gestational periods were associated with higher odds of unstable growth trajectories.

Collagen in the tumor microenvironment plays diverse biological roles, from serving as the structural framework of tumors to influencing immune responses, angiogenesis, and tumor progression. Consequently, developing strategies to optimize the suppression of collagen’s promotive effects on tumor growth while maintaining its inhibitory functions on tumor initiation has become a key focus of cancer research and therapy. A significant challenge remains in identifying a biomarker with both high sensitivity and specificity for cancer diagnosis. This review, therefore, highlights the substantial value and clinical relevance of collagen as a biomarker throughout cancer onset and progression. It explores the fundamental link between collagen and immunotherapeutic outcomes, further illustrating how targeting collagen—along with its interactions with tumors and immune cells—can offer more reliable predictive markers for personalized immunotherapy. This approach ultimately enables the development of more tailored and standardized treatment regimens for patients with cancer.

BackgroundThere is a growing body of evidence indicating that metabolites are associated with an increased risk of cardiovascular diseases (CVDs), the underlying causality of these associations remains largely unchallenged. Given the inherent difficulty in establishing causality using epidemiological data, we employed the technique of Mendelian randomization to investigate the potential role of plasma metabolite factors in influencing the risk of CVDs.MethodsThe exposure was based on 1,400 plasma metabolites, and outcomes involved four CVD datasets from public databases. Initial causality was assessed by inverse variance weighting (IVW), followed by sensitivity analyses using MR-Egger regression, weighted median, and Multiple Effectiveness Residual Sums and Outliers (MR-PRESSO) method. Potential heterogeneity and multivalence were assessed using the MR-Egger intercept and Cochran's Q statistic. After Bonferroni correction, causal associations were found to be significant with p-values less than 0.05. All statistical analyses were rigorously executed in R software.ResultsOur findings identified causal relationships between 15 metabolites and cardiovascular disease. Of these, 4 were associated with AA (aortic aneurysm), 7 with atrial fibrillation and flutter, 2 with HF (heart failure), and 3 with stroke.ConclusionThis is the first systematic mendelian randomization analysis using genome-wide data to assess the causal relationship between serum metabolites and different cardiovascular diseases, providing preliminary evidence for the impact of lipid metabolism disorders on cardiovascular disease risk.

Reproductive tract diseases have become a serious public health problem threatening women’s health. Vaginal microecological balance in women of childbearing age is essential for the maintenance of reproductive health, and different environmental conditions may have an impact on the composition of the vaginal microbial community and its metabolites. This is particularly true at different altitudes. Changes in environmental factors with increasing altitude may lead to vaginal microecological imbalances that increase the risk of reproductive tract infections and other gynecological diseases. Therefore, it is important to study vaginal microbial communities and metabolites in women of reproductive age at different altitudes. In this study, 16 S rDNA sequencing and non-targeted metabolomics of vaginal secretions from healthy women of childbearing age at different altitudes were performed to analyze the composition of vaginal flora and metabolites of normal women of childbearing age at different altitudes, with the aim of providing new ideas for the prevention, diagnosis and treatment of diseases caused by vaginal microecological imbalance in women of childbearing age. General clinical data and vaginal secretions of a total of 60 healthy women of childbearing age were collected from four regions, namely, the low altitude group (8 m above sea level), the middle altitude group (2,000 m above sea level), the middle-high altitude group (2,800 m above sea level), and the same as the high altitude group (4,000 m above sea level), and were analyzed by sequencing of the V3-V4 region of the 16 S rDNA and untargeted metabolomics sequencing. 16 S rDNA sequencing can be used to comprehensively analyze the reproductive tract flora of women of childbearing age at different altitudes; the vaginal flora of normal women of childbearing age is dominated by the phylum Thick-walled Bacteria and Lactobacillus spp. The α-diversity of the vaginal flora increases with the elevation of altitude but there is no statistically significant difference; with the elevation of altitude, the percentage of the specialized anaerobic flora in the vagina is higher among the genera of Porphyromonas, Anaerobic Coccidia, and Peptostreptococcus. anaerobic increased in the vagina. Non-targeted metabolomics analysis revealed that there were differences in vaginal metabolites among women of childbearing age at different altitudes, with energy metabolism and nutrient metabolism being the main ones. Analysis of the four groups of differential metabolites showed that Ectoine, Thiamine, Taurine, D-glucono-1,5-lactone, 2-oxoadipic acid and N-Acetylserotonin differed significantly in the distribution of the four groups and were significantly elevated in the vaginas of women at high altitude. With the increase of altitude, the diversity of vaginal flora of women of childbearing age increased, and at the same time, there were differences in vaginal metabolites at different altitudes, which were hypothesized to be related to factors such as hypoxia, high altitude, and differences in hygiene habits in the plateau. The relationship between this and high altitude and reproductive tract diseases will be further explored in the future to provide theoretical guidance for improving the reproductive health of women of childbearing age in highland areas.

Nitric oxide (NO) modulates several cancer-related physiological processes and has advanced the development of green methods for cancer treatment and integrated platforms for combination or synergistic therapies. Although a nanoengineering strategy has been proposed to overcome deficiencies of NO gas or small NO donor molecules, such as short half-life, lipophilicity, non-selectivity, and poor stability, it remains challenging to prepare NO nanomedicines with simple composition, multiple functions and enhanced therapeutic efficacy. Herein, we build a liquid metal nanodroplet (LMND)-based NO nanogenerator (LMND@HSG) that is stabilized by a bioreducible guanylated hyperbranched poly(amido amine) (HSG) ligand. Mechanically, the tumor microenvironment specifically triggers a cascade process of glutathione elimination, reactive oxygen species (ROS) generation, and NO release. According to actual demand, the ROS and NO concentrations could be readily controlled by tuning the LMND and HSG feed amounts. Along with the intrinsic anticancer property of LMND (ROS-mediated apoptosis and anti-angiogenesis), LMND@HSG administration could further enhance tumor growth suppression compared with LMND and HSG alone. From this study, leveraging LMND for NO gas therapy provides more possibilities for the prospect of LMND-based anticancer nanomedicines.

Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD+) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.

Per- and polyfluoroalkyl substances (PFAS) are widespread persistent pollutants and pose a risk to human health. However, the transfer efficiencies (TEs) of PFAS from source water into maternal serum, and its metabolic pathways linking PFAS exposure and human disease are remain unclear. Here, we present an integrative study combining multi-water and serum PFAS analysis, lipidomics, and machine learning to decipher TEs and PFAS-metabolism interactions. Analyzing 30 PFAS across source water (N = 18), tap water (N = 18), water during drinking water treatment process (DWTP, N = 12), and serum of pregnant women alongside 297 lipid species, we developed a SHAP (Shapley Additive Explanations) framework to quantify PFAS origins and serum-specific lipid responses. We found PFAS were prevalent in source water samples, with PFBA, PFPeA, 6:2 FTS, PFOA, and PFOS being predominant chemicals. In addition, DWTP may not be effective in removing PFAS, with most of target chemicals tested exhibiting removal below 50 %. Moreover, source water outperforms tap water in predicting maternal serum PFAS concentrations, suggesting source water contamination reflects maternal exposure more directly. Machine learning further showed that maternal serum lipid metabolism was influenced by PFAS, such as HFPO-DA and N-MeFOSAA mainly disrupted glycerphospholipid homeostasis (e.g., PC and LPC), highlighting risks to maternal metabolism. Our findings pioneer AI-driven tracing of PFAS transfer dynamics and lipidomic disruptions, warranting a comprehensive strategy beyond drinking water to handle water PFAS contamination.

BackgroundThe estrogen-related receptor family genes (ERRs), including ESRRA, ESRRB, and ESRRG, have been implicated in a few tumors, exhibiting distinct roles through diverse mechanisms. The purpose of our research is to explore the commonalities and underlying mechanism of ERRs in malignancies from a pan-cancer perspective and to validate the role and mechanisms of ESRRG in gallbladder cancer (GBC).MethodsWe leveraged public databases such as TCGA and GTEx to systematically investigate the potential functions of ERRs in malignancies. ESRRG expression was analyzed through immunohistochemical staining in gallbladder cancer and cholecystitis tissues. For functional validation, ESRRG was knocked down in GBC cell lines, followed by CCK-8, colony formation, scratch wound healing, Transwell migration, and invasion assays. Western blot, qPCR, and immunofluorescence were performed to evaluate the relationship between ESRRG, PD-L1, and CD8+ T cells.ResultsCompared to adjacent normal tissues, ESRRA is overexpressed in most tumors, ESRRB is generally underexpressed, and ESRRG exhibits significant expression alterations across various tumors. All three ERRs demonstrate significant prognostic value across different cancers. Notably, the strong associations of ERRs with key immunological features—stromal scores, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB)—suggest their involvement in immune evasion and their potential utility in guiding immunotherapy strategies. All three ERRs display a positive correlation with advanced tumor stages in cholangiocarcinoma (CHOL). Specifically, in CHOL, ESRRG expression is closely associated with lymphatic metastasis, poorer overall survival, reduced immune infiltration, elevated PD-L1 expression, epithelial-mesenchymal transition (EMT), and DNA damage response. In GBC tissues, we subsequently confirmed that ESRRG expression positively correlates with pathological staging and PD-L1 expression, while negatively correlating with prognosis and CD8+ T cell infiltration. Knockdown of ESRRG in gallbladder cancer cells results in decreased proliferation, migration, and invasion. Moreover, the expression of PD-L1, MSH2, BRCA1, MMP2, and VIMENTIN decreased with ESRRG knockdown. ConclusionOur pan-cancer analysis reveals ERRs as critical regulators of tumor immunity and progression, with ESRRG emerging as a key oncogenic driver in GBC. The mechanistic link between ESRRG and PD-L1/EMT suggests its potential as a therapeutic target to enhance immunotherapy efficacy. These findings underscore the need for tissue-specific targeting strategies for ERR family members in precision oncology.

In the original publication [...].

Cholangiocarcinoma (CCA) arises within the peritumoral bile microenvironment, yet microbial translocation from bile to intracholangiocarcinoma (IntraCCA) tissues remains poorly understood. Previous studies on bile microbiota alterations from biliary benign disease (BBD) to CCA have yielded inconsistent results, highlighting the need for cross-study analysis. We presented a comprehensive analysis of five cohorts (N = 266), including our newly established 16S rRNA gene profiling (n = 42), to elucidate these microbiota transitions. The concordance of bacteria between CCA bile and intraCCA tissue, represented by Enterococcus and Staphylococcus, suggested microbiota migration from bile to intratumoral tissues. A computational random forest machine learning model effectively distinguished intraCCA tissue from CCA bile, identifying Rhodococcus and Ralstonia as diagnostically significant. The model also excelled in differentiating CCA bile from BBD bile, achieving an AUC value of 0.931 in external validation. Using unsupervised hierarchical clustering, we established Biletypes based on microbial signatures in our cohort. A combination of 17 genera effectively stratified patients into Biletype A and Biletype B. Biletype B robustly discerned CCA from BBD, with Sub-Biletype B1 correlating with advanced TNM stage and poorer prognosis. Among the 17 genera, bacterial Cluster 1, composed of Sphingomonas, Staphylococcus, Massilia, Paenibacillus, Porphyrobacter, Lawsonella, and Aerococcus, was enriched in Biletype B1 and predicted CCA with an AUC of 0.96. Staphylococcus emerged as a promising single-genus predictor for CCA diagnosis and staging. In conclusion, this study delineates a potential microbiota transition pathway from the gut through CCA bile to intra-CCA tissue, proposing Biletypes and Staphylococcus as biomarkers for CCA prognosis.

INTRODUCTION:Recurrent spontaneous abortion (RSA) is associated with maternal-fetal interface dysfunction, particularly abnormal trophoblast invasion and proliferation. However, our understanding of the cause of RSA remains limited. METHODS:Plasma Trp and Kyn levels were measured in two groups using enzyme-linked immunosorbent assay. Immunofluorescence and western blot analyses were employed to evaluate the expression of IDO1, VEGFA, and proteins associated with epithelial-mesenchymal transition (EMT) in villous and decidual tissues from patients with RSA. The effects of Tryptophan (Trp) and IDO1-driven Trp-Kynurenine (Kyn) metabolism on trophoblast proliferation, migration, EMT, and angiogenesis were investigated in the HTR-8/SVneo cell line using wound healing, transwell migration, quantitative real-time PCR (RT-qPCR), Western blotting, and tube formation assays. RNA sequencing (RNA-seq) identified differentially expressed genes in cells treated with 500 μM exogenous L-Trp. RESULTS:RSA patients exhibited elevated plasma Trp levels and significantly reduced Kyn levels, indicating decreased IDO1 activity (as assessed by the Kyn/Trp ratio) compared to controls. IDO1, EMT-related proteins, and VEGFA were downregulated in RSA patient tissues. In vitro, L-Trp enhanced trophoblast migration, invasion, EMT, and microvasculature formation via IDO1 activation. The reduced functional capabilities induced by the IDO1 antagonist 1-MT (500 μM) were rescued by Kyn (300 μM). RNA-seq revealed that L-Trp upregulation modulates trophoblast gene expression and functional pathways associated with amino acid metabolism, angiogenesis, and vasculature development. DISCUSSION:Our study reveals a novel molecular mechanism by which Trp metabolism regulates HTR-8 cell function, suggesting that modulating IDO1 activity may represent a therapeutic strategy to improve trophoblast function and pregnancy outcomes in RSA.

Emerging nanodrug delivery strategies seek to overcome tumor heterogeneity and enhance drug penetration in the dense matrix of solid tumors. This study presents a dual-responsive nanoplatform, poly(lactic-co-glycolic acid)-disulfide-polyethylene glycol-glutamate (PLGA-SS-PEG-Glu) loaded with Gambogic acid (GA), engineered to exploit γ-glutamyltranspeptidase (GGT) and glutathione (GSH) triggers specific to the triple-negative breast cancer (TNBC) microenvironment. Designed with Boc-L-Glutamic Acid-1-tert-butyl ester (Boc-Glu-OtBu), this nanoplatform achieves enzyme-triggered charge reversal to enhance tumor penetration, facilitating GGT-induced charge-switching and GSH-responsive GA release. In vitro, PLGA-SS-PEG-Glu@GA shows potent cytotoxicity (IC50 = 0.80 μg/ml) against 4T1 TNBC cells, inducing apoptosis and inhibiting cell proliferation through energy-dependent, GGT-mediated endocytosis. Compensatory Nrf2/HO-1 activation mechanistically induced by GA-loaded nanoplatform ultimately potentiated mitochondrial apoptotic pathway (Bcl-2/caspase-3) initiation, promoting apoptosis. In vivo, this nanoplatform leveraged its tumor-specific enzymatic and redox microenvironment-responsive properties to achieve enhanced deep intratumoral penetration. Treatment for 2 weeks effectively suppressed primary tumor growth, while extended therapy to one month significantly inhibited the formation of pulmonary metastatic foci. This dual-responsive strategy not only elevates drug bioavailability at the tumor site but also provides a promising solution to overcome critical barriers in solid tumor drug delivery.

The consistency of the associations between the breast microbiome and breast cancer (BC) across various studies remains uncertain. Publicly accessible data sets from five BC studies, comprising 16S rRNA gene sequencing data from 161 BC tissues (BC_tissue), 195 BC adjacent non-cancerous tissues (BC_adjacent), and 451 normal breast tissues (normal_tissue), were retrieved from the European Nucleotide Archive. Overall, the microbial composition across the three breast tissue statuses was predominantly characterized by the phyla Proteobacteria and Firmicutes, a distribution likely attributable to the fatty acid-rich environment of the breast tissue. Comparative analysis revealed that the relative abundances of the genera Cutibacterium and Burkholderia were significantly increased in both BC_adjacent and normal_tissue compared to BC_tissue. This observation suggested a potential anticancer effect associated with these genera. Our analysis revealed a significant reduction in the abundance of Cutibacterium and Cutibacterium acnes in BC tissues, which served as specific diagnostic features for BC. This finding was corroborated by our in-house data set (n = 28), which yielded similar conclusions. Subsequent in vitro and in vivo experiments verified the potential antitumor effects of C. acnes supernatant in BC. In conclusion, our study highlighted the predictive capacity of microbial biomarkers in the onset of BC. Notably, specific bacterial species within the breast microbiome, such as Cutibacterium and C. acnes, exhibited potential as diagnostic markers for BC and may contribute significantly to antitumor activity. Nevertheless, the molecular mechanisms governing their interactions with cancer cells are not yet fully understood, necessitating further research to investigate their viability as targets for tumor prevention.IMPORTANCEAlthough a growing number of studies have highlighted the significant role of microorganisms in BC, there is a lack of consensus regarding the specific microbial genera consistently associated with breast cancer. While some studies have identified certain genera in the breast cancer environment, the results are often inconsistent and influenced by factors such as study design, population, or methodologies used. Through a comprehensive analysis of five publicly available breast cancer studies, along with validation from an in-house cohort, we found a significantly reduced abundance of Cutibacterium and C. acnes in BC tissues. In vivo and in vitro experiments demonstrated the antitumor effects of C. acnes in BC. Understanding the antitumor mechanisms of C. acnes in BC may provide potential avenues for developing novel therapeutic strategies for this disease.