Introduction Inadequate and conflicting reporting exists regarding the intricate association between positive lymph node (PLN) number and papillary thyroid cancer (PTC) survival. Our aim was to elucidate the relationships between PLN and overall survival in PTC patients using a large population-based study. Methods Data on PTC patients diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Proportional hazards regression models with restricted cubic splines (RCS) were employed to examine the associations between them. Multivariable adjusted Cox regression models and sensitivity analyses were conducted to validate the association. Results In total, 44,181 patients with PTC were included (18,148 with and 26,033 without lymph node metastases). After adjusting for covariate effects, patients with node metastases exhibited compromised survival compared to those without (hazard ratio[HR], 1.58; 95% confidence interval [CI], 1.44 to 1.74). In the RCS model, all-cause mortality risk increased rapidly until seven PLN, with a HR of 1.14 (95% CI, 1.11 to 1.17) per increase of one metastatic node but stabilized afterwards (HR, 1.01; 95% CI, 0.98 to 1.05) ( P for non-linearity <0.001). Furthermore, multivariate Cox models and sensitivity analyses confirmed similar correlations between the PLN count and overall survival. Conclusions Our study suggests an evident non-linear association between PLN number and overall survival in PTC patients, suggesting a potential threshold of seven or fewer PLN to have better survival outcome.

BACKGROUND:Concurrent chemoradiotherapy is the standard adjuvant treatment for cervical cancer patients with pathologically confirmed lymph node metastases (International Federation of Gynecology and Obstetrics 2018 stage IIIC1p or IIIC2p) after radical surgery. Yet distant metastasis remains the predominant pattern of failure. In recent years, Immune checkpoint inhibitors combined with platinum-containing chemotherapy has been increasingly valued in the treatment of cervical cancer. Yet the role of postoperative chemo-immunotherapy in this setting remains unclear. There is no high-quality evidence-based evidence. METHODS:This multicenter, prospective, single-arm phase II clinical trial is to evaluate the safety and preliminary efficacy of postoperative chemo-immunotherapy in cervical cancer patients with pathologically confirmed lymph node metastasis after radical hysterectomy, and to explore potential biomarkers associated with treatment response. Fifty-nine carefully selected cervical cancer patients with pathologically confirmed lymph node metastases and programmed death ligand-1 positivity (combined positive score ≥1) after radical surgery will be enrolled. Postoperative treatment is initiated 2-3 weeks after surgery. Each treatment cycle is administered every 21-28 days and consists of chemotherapy (paclitaxel 175 mg/m², cisplatin 75-80 mg/m²) combined with camrelizumab (200 mg). Patients with 3 or more positive lymph nodes or para-aortic lymph node metastases receive 6 cycles of combined chemo-immunotherapy, whereas other patients receive 3 cycles. The primary outcome is 3-year disease-free survival rate. The secondary outcomes are overall survival rate, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT07167160.

BackgroundAcute cholecystitis is a common abdominal condition mainly caused by enteric Gram-negative bacilli and Enterococcus species. Advances in microbial detection have highlighted infections by rare pathogens like Shewanella putrefaciens (S. putrefaciens), an opportunistic bacterium from aquatic environments affecting mainly immunocompromised or comorbid patients. Its clinical features, antibiotic resistance, and treatment remain unclear.Case presentationThis article presents a case study of an 87-year-old female patient with a medical history of gallstones and previous endoscopic retrograde cholangiopancreatography (ERCP), who was admitted to the hospital due to “low back and leg pain.” On November 14, 2023, she developed acute cholecystitis. Initial treatment consisted of cefoperazone/sulbactam and ciprofloxacin. Ultrasound-guided percutaneous transhepatic gallbladder drainage (PTGBD) was performed, revealing purulent bile that tested positive for S. putrefaciens and Enterococcus faecium (E. faecium). Based on susceptibility testing, the antibiotic regimen was adjusted to cefoperazone/sulbactam and vancomycin, which was administered until November 24, 2023. The patient’s condition subsequently improved, and she was discharged from the hospital.ConclusionWe documented the inaugural case of an elderly patient presenting with acute cholecystitis co-infected with S. putrefaciens and E. faecium. This case underscores the importance of integrating source control via PTGBD with targeted antimicrobial therapy guided by drug susceptibility testing, highlighting their synergistic role in effective management. Furthermore, the monitoring of procalcitonin (PCT) levels offers valuable support for clinical decision-making.

Respiratory diseases pose a significant global public health challenge. Extensive research indicates that respiratory conditions are influenced by lung microbiota; however, the relationships between alterations in pulmonary microbiota and various respiratory diseases remain unclear. This study explores the characteristics and distinctions of lung microbial communities in patients with lung cancer (LC), chronic obstructive pulmonary disease (COPD), and community-acquired pneumonia (CAP). The research involved 114 patients and employed culturomics and 16S rRNA gene sequencing to analyze bronchoalveolar lavage fluid samples. Through culturomics, 168 bacterial species were identified, with variations in bacterial profiles observed across the different diseases. Sequencing results indicated that the dominant phyla among the three groups were Bacillota, Bacteroidota, Pseudomonadota, Actinomycetota, and Fusobacteriota, consistent with the culturomics findings. Notably, the CAP group exhibited higher species richness compared to the LC and COPD groups, with significant differences in beta-diversity among the three groups. Specific bacterial genera, such as Alloprevotella, Abiotrophia, and Mycoplasma, were distinguished as indicative taxa for the LC, COPD, and CAP groups, respectively. Utilizing random forest modeling and receiver operating characteristic curve analysis, several key bacterial genera were identified as capable of differentiating between these diseases. The study highlights distinct differences in lung microbiota among patients with LC, COPD, and CAP, potentially serving as a reference for diagnosis, suggesting that disease-specific microenvironments may influence local microbial communities, thus providing evidence for associations between lung microbiota and various respiratory diseases that warrant further investigation.IMPORTANCEThe human lung microbial community plays a crucial role in various respiratory diseases by regulating the lung's immune system and maintaining lung homeostasis. However, there is a paucity of comparative studies examining the characteristics of the pulmonary microbiome in common respiratory diseases, such as lung cancer (LC), chronic obstructive pulmonary disease (COPD), and community-acquired pneumonia (CAP). This study aims to explore the differences in lung microbiomes among these conditions. By employing culturomics and 16S rRNA sequencing technology, we identified significant variations in their lung microbiota. Notably, Alloprevotella, Abiotrophia, and Mycoplasma were identified as indicative taxa for the LC, COPD, and CAP groups, respectively. This research is essential for enriching the database of cultivable lung bacteria and investigating the interactions between specific strains and diseases at the species level, and identifying potential biomarkers and therapeutic targets.

Accurate classification of focal liver lesions is crucial for diagnosis and treatment in hepatology. However, traditional supervised deep learning models depend on large-scale annotated datasets, which are often limited in medical imaging. Recently, Vision-Language models (VLMs) such as Contrastive Language-Image Pre-training model (CLIP) has been applied to image classifications. Compared to the conventional convolutional neural network (CNN), which classifiers image based on visual information only, VLM leverages multimodal learning with text and images, allowing it to learn effectively even with a limited amount of labeled data. Inspired by CLIP, we pro-pose a Liver-VLM, a model specifically designed for focal liver lesions (FLLs) classification. First, Liver-VLM incorporates class information into the text encoder without introducing additional inference overhead. Second, by calculating the pairwise cosine similarities between image and text embeddings and optimizing the model with a cross-entropy loss, Liver-VLM ef-fectively aligns image features with class-level text features. Experimental results on MPCT-FLLs dataset demonstrate that the Liver-VLM model out-performs both the standard CLIP and MedCLIP models in terms of accuracy and Area Under the Curve (AUC). Further analysis shows that using a lightweight ResNet18 backbone enhances classification performance, particularly under data-constrained conditions.

Background:There is growing evidence that long non-coding RNAs (lncRNAs) play crucial roles in cancer progression and therapy. Our previous study showed that the lncRNA plasmacytoma variant translocation 1 (PVT1) regulates tumor growth and metastasis in breast cancer (BC). As a conventional chemotherapeutic drug, doxorubicin (DOX) resistance continues to be a major challenge in BC treatment. This study aimed to explore the role and underlying mechanism of PVT1 in doxorubicin-resistant BC. Methods:Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) were carried out to detect gene and protein expression levels. The extent of ferroptosis was measured based on the cellular glutathione (GSH) levels and total or lipid reactive oxygen species (ROS) levels. An in-situ tumor implantation model in nude mice was employed to validate the mechanism in vivo. Transcriptome analysis was conducted to identify downstream target genes. Results:This study found that PVT1 was highly expressed in the plasma of drug-resistant patients and drug-resistant cell lines. Silencing PVT1 reduced cellular glutathione level, increased reactive oxygen species (ROS) and lipid peroxidation (LPO), while ferroptosis inhibition in rescue experiments partially reversed the oxidative stress. In-vivo study confirmed that silencing PVT1 increased the sensitivity of BC cells to doxorubicin treatment. Transcriptomic sequencing revealed that solute carrier family 3 member 2 (SLC3A2) was the most potential target gene of PVT1, which was confirmed in PVT1-silenced cell models. Conclusion:Mechanistically, PVT1 increased SLC3A2 expression, thus inhibiting ferroptosis and promoting doxorubicin resistance in BC, indicating that PVT1 could be a promising therapeutic target for doxorubicin-resistant BC patients.

This study aimed to explore the geographic distribution and risk clusters of cervical cancer incidence from 2020 to 2021 in Shandong, China, and to detect the differences between urban and rural areas. Our data were obtained from the cervical cancer incidence reports of 136 tumor registration areas. The population data is sourced from the police household registration records and statistical yearbooks. The distribution of incidence was displayed with GIS-based maps at the county level. The results showed the incidence rates aggregation area mainly concentrated in the medium and eastern part of the province, we also observed differences in the geographic distribution and risk clusters between urban and rural areas. Additionally, four significant risk clusters have been identified, with the most likely cluster located in the medium and eastern regions, these results are helpful in formulating effective and targeted prevention and control strategies for different regions.

Background Breast cancer is the leading cause of cancer-related mortality among women. Laminin subunit alpha 3 (LAMA3), a constituent of the extracellular matrix, is associated with tumor progression. However, its clinical relevance and function remain inadequately understood. Methods We conducted a systematic evaluation of LAMA3 expression in breast cancer by assessing plasma, cell lines, and tissues using mass spectrometry, qRT-PCR, Western blotting, and immunohistochemistry (IHC). The colocalization of LAMA3 with tumor and stromal markers was detected by immunofluorescence. Tumor and stromal regions were digitally segmented using QuPath software to compute compartment-specific histochemical scores. The correlation of LAMA3 with clinical characteristics was evaluated using Chi-square and nonparametric statistical tests. The impact of LAMA3 expression on survival was analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. Bioinformatics analyses were performed to investigate potential underlying mechanisms. Results Plasma LAMA3 protein levels were elevated in patients, but its mRNA and protein levels were reduced in breast cancer cell lines and tissues. Analysis on TIMER 2.0 database showed LAMA3 was positively related to cancer-associated fibroblasts and epithelial cells infiltration in breast cancer tissues. Multiplex immunofluorescence revealed LAMA3 colocalized with cancer-associated fibroblasts and tumor epithelial cells. Although LAMA3 protein levels were reduced in breast cancer tissues, high stromal—but not tumor—LAMA3 expression was significantly associated with advanced histological grade, TNM stage, molecular subtype, recurrence, and poorer survival outcomes. Multivariate analysis indicated stromal LAMA3 as an independent prognostic factor for survival in breast cancer, with enhanced predictive power when combined with lymph node metastasis. Bioinformatic analyses suggested that LAMA3 protein was correlated with epithelial-mesenchymal transition and extracellular matrix-receptor interaction pathways in breast cancer. Conclusions Stromal LAMA3, expressed in the tumor microenvironment, is a new potential prognostic biomarker for breast cancer, emphasizing the significance of spatial context in biomarker discovery and suggesting its use in risk stratification.

OBJECTIVE:To establish a better triage strategy using SOX1/PAX1 methylation detection for high-risk HPV (hrHPV)-positive women than cytology. DESIGN:A cohort study. SETTING:Population-based cervical cancer (CC) screening cohort. POPULATION:A total of 5684 women were enrolled. METHODS:SOX1/PAX1 methylation was detected by quantitative methylation-specific PCR using cytologic residue from hrHPV-positive women at baseline in a 3-year CC screening cohort. Risk stratification ability was evaluated by the immediate and cumulative cervical intraepithelial neoplasia (CIN) grade 2/3 or worse (CIN2+/3+) risks. MAIN OUTCOME MEASURES:CIN3+ and CIN2+. RESULTS:At baseline, 682 hrHPV-positive women were included with 63 CIN2+ and 39 CIN3+. Over 3 years, 109 CIN2+ and 62 CIN3+ were detected. Methylation demonstrated better risk stratification than cytology among hrHPV-positive women. When compared with current practice triage strategy (Strategy A), post hoc re-triage analysis showed that methylation triage for all hrHPV-positive women (Strategy C) significantly increased sensitivity (97.44%/83.87% vs. 84.62%/64.52%, p = 0.0476/0.014), specificity (83.36%/85.00% vs. 73.41%/73.55%, p = < 0.001/< 0.001), positive predictive value (26.21%/35.86% vs. 16.18%/19.61%, p = 0.022/0.001), and negative predictive value (99.81%/98.14% vs. 98.74%/95.40%, p = 0.040/0.012) in detecting immediate and 3-year cumulative CIN3+. Similar improvements were observed for methylation triaged for HR12-positive (Strategy B) and for combined HPV and cytology primary screening (Strategy D). More importantly, all methylation-based triage strategies reduced colposcopies and postponed follow-up intervals compared to Strategy A over the 3-year period of CC screening. CONCLUSION:SOX1/PAX1 methylation showed better risk stratification compared with cytology and enabled more efficient management of HPV-positive women, though external validation and head-to-head comparisons with other triage methods are needed.

Tendon-derived stem cells (TDSCs) are a unique cell population found in tendons, exhibiting both mesenchymal stem cell (MSC)-like phenotypes and tendon-specific markers. They have emerged as a promising research tool in tendon-related tissue engineering studies. However, there is currently no well-characterized TDSC line with MSC-related phenotypes for investigating tendon biology or developing therapeutics. Here, we established an immortalized monoclonal TDSC, named iTDSC#6, from the Achilles tendon of an adult male Sprague-Dawley rat. Cell clones were characterized for MSC-associated cell surface markers, colony formation capacity, and trilineage differentiation potentials, tenogenic potential and SV40LT expression at both early (passage < 10) and late (passage > 30) stages. iTDSC#6 showed stable expression of Simian virus 40 large T antigen (SV40LT) and demonstrated similar MSC-like phenotypes as its wild-type counterpart at both early and late passages, including colony formation capability and multi-lineage differentiation potentials. iTDSC#6 was positive for the MSC markers CD90, CD44, CD29 and CD73 (≥95%) and negative for the hematopoietic markers CD34 and CD45 (<1%). Regarding its utility for basic research and therapeutic development, iTDSC#6 showed potential for modelling cells with increased levels of senescence-associated beta-galactosidase activity in response to hydrogen peroxide and for bioengineering scaffold-free, tendon-like 3D constructs as evidenced by its upregulation of tendon-related markers, high nuclear aspect ratio, and aligned collagen organization. In conclusion, an immortalized TDSC line was successfully established that shows promise as a useful research tool to study tendon biology and aid the development of therapeutics for tissue engineering and regenerative medicine.

Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage-dependent methionine-S-adenosylmethionine (SAM)-protein arginine methyltransferase 1 (PRMT1)-lactate dehydrogenase A (LDHA)-lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti-inflammatory interleukin-10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation-associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709-specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post-translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.

Integration of high-risk human papillomavirus into specific loci of the genome is a pivotal event in cervical carcinogenesis; however, it’s underlying mechanism remains largely undefined. Here, through establishing an 8q24 site-specific HPV18 gene knock-in cell model by utilizing the CRISPR/Cas9 system, we discover that HPV18 knock-in (HPV-KI) results in a global alteration of the genome’s topologically associating domain structure and an up-regulation of cancer-related genes in HPV- HaCaT cells, among which the significantly up-regulated IL-17 signaling pathway and S100A8/A9 are partitularly prominent. Further mechanistic study demonstrate that HPV-KI reprograms metabolic pathway, especially up-regulates glycolysis and subsequently facilitates glycerolipid synthesis in HaCaT cell, leading to sphingosine-1-phospate (S1P) secretion and enhanced SpHK1/S1P/S1PR1 signaling pathway, thereby activating the the MAPK and NF-κB signaling pathways followed by inducing the expression of S100A8/A9, and hence induces the malignant transformation of cells. Importantly, inhibition of the S1P/S1PR1 signaling pathway down-regulates the expression of S100A8/A9 and suppresses the growth of HPV-KI cells and xenograft derived from cervical cancer patient. These findings provide novel insights into HPV integration-induced cervical carcinogenesis and identify potential therapeutic targets for its treatment.

BACKGROUND:Gastric-type adenocarcinoma (GAC) is the predominant subtype of HPV-independent endocervical adenocarcinoma, characterized by aggressive clinical behavior and poor prognosis. However, its tumor immune microenvironment (TIME) remains largely unexplored. METHODS:We systematically profiled the immune landscape using bulk RNA sequencing and multiplex immunofluorescence staining and comprehensively analyzed the associations between immune features, clinicopathological parameters, and patient outcomes in a multi-institutional cohort of 153 GAC cases. RESULTS:GAC tumors exhibited sparse T cell but abundant macrophage infiltration, predominantly with M2-polarized macrophages in advanced stage. Tumors with tertiary lymphoid structure (TLS) demonstrated an immunosuppressive milieu characterized by enrichment of B cells, PD1-CD8+ T cells, and regulatory T cells. While TLS-positive patients were associated with poorer prognosis, 2 patients showed improved survival with chemoradiotherapy. Moreover, the TLS and FIGO stage-based prognostic model was robust in the risk stratification for tumor recurrence. CONCLUSIONS:We reveal a distinct immunosuppressive TIME and TLS in GAC. TLS might confer an adverse prognosis. Our findings provide valuable clues for individualized therapy for this aggressive cancer in future.

Although oncolytic virus therapy has shown promising efficacy in preclinical studies, its clinical translation remains limited because conventional experimental models fail to replicate the human tumor microenvironment accurately. As an advanced three-dimensional culture system, organoid technology provides a powerful platform to address this challenge, as it retains the heterogeneity and microenvironmental features of primary tumors. This review systematically summarizes organoid modeling technology and highlights its critical role in the research and development of oncolytic viruses. The development of organoid biobanks, together with their integration into high-throughput screening systems, has facilitated rational viral engineering and targeted optimization through large-scale data analysis. In clinical applications, patient-derived organoids have enabled personalized prediction of therapeutic responses by serving as functional models for drug testing. Despite ongoing challenges in protocol standardization and in accurately simulating the immune microenvironment, organoid technology is rapidly becoming a key bridge between basic research and clinical translation in oncolytic virotherapy, accelerating the development of next-generation oncolytic virus therapies.

ABSTRACT:Gynecological tumors are a group of prevalent and highly lethal malignancies affecting the female reproductive system. The immunosuppressive tumor microenvironment, characterized by immune cell dysfunction and inhibitory cytokine dysregulation, plays a pivotal role in tumor initiation, progression, and resistance to conventional therapies. Although standard treatments-including surgery, radiotherapy, and chemotherapy-remain the mainstay for early-stage disease, they often fail to manage advanced, recurrent, or drug-resistant tumors. In recent years, immunotherapy has emerged as a transformative approach in cancer treatment, offering new hope for patients with gynecological malignancies. Notably, immune checkpoint inhibitors, adoptive cell therapy, and cancer therapeutic vaccines have exhibited encouraging efficacy across several clinical trials. This review systematically summarizes recent advances in immunotherapy for major gynecological cancers, including cervical cancer, endometrial cancer, and ovarian cancer. We focus on the immunological landscape of these tumors, the underlying mechanisms of immune-based therapies, key clinical findings, and current challenges. In addition, we highlight future research directions and explore prospects for personalized immunotherapy, aiming to provide both theoretical insight and practical guidance for clinical translation.

Human papillomavirus type 16 (HPV16) causes over 50% of HPV-related cervical cancers. With the widespread use of virus-like particle (VLP)-based HPV prophylactic vaccines, investigating the differences in viral assembly, infectivity and antigenic properties among different variants is highly important for further eliminating diseases caused by HPV. We analyzed HPV16 L1 protein sequences from the NCBI database and identified 14 representative clusters. Pseudovirus (PsV) formation, infectivity, and susceptibility to vaccines were assessed for these variants, and molecular dynamics (MD) simulations and modified enzyme-linked immunosorbent assays (ELISAs) were ultimately employed to investigate the underlying mechanisms. The sequence identical to P03101 in the UniProt database served as the reference (P16_WT). Among the 13 variants, five presented reduced PsV packaging efficiency to varying degrees, which correlated with diminished L1 protein expression. Compared with P16_WT, the remaining eight variants successfully produced infectious PsVs with high titers and exhibited equivalent infectivity in epithelial cells. Neutralization assays revealed that four variants demonstrated varying levels of decreased susceptibility to vaccines; notably, P16_5 and P16_13 exhibited significantly reduced sensitivity to all three vaccines. MD simulation and modified ELISA indicated that this reduction results from the unstable binding interactions between the L1 variants and the antibodies. Importantly, key residues in these less susceptible variants, such as P16_5 and P16_13, were under positive selection prior to the commercialization of these vaccines. Our findings demonstrated that a significant proportion of globally circulating HPV16 L1 variants currently display diminished susceptibility to available vaccines. Consequently, ongoing surveillance of HPV variants is imperative.

The Wnt signaling pathway is broadly categorized into two major classes: Canonical and non-canonical pathways. The canonical Wnt pathway, which is also referred to as the Wnt/β-catenin pathway, involves the nuclear translocation of β-catenin. By contrast, non-canonical Wnt pathways, including the Wnt/Ca2+ pathway and the Wnt/planar cell polarity pathway, function independently of β-catenin nuclear translocation. Among these non-canonical pathways, the Wnt/Ca2+ pathway influences cellular behavior by elevating intracellular Ca2+ concentrations. This pathway primarily regulates cytoskeletal remodeling, cell migration, polarity and immune responses, and serves a crucial role in cell proliferation, differentiation, embryonic development and tumorigenesis. Notably, Wnt/Ca2+ signaling exhibits dual functions in different tumor types, promoting tumorigenesis in certain cancers, whilst inhibiting it in others. The present review systematically summarizes research regarding the Wnt/Ca2+ signaling pathway, elucidates its mechanisms in cancer progression, and outlines current strategies for targeting the Wnt/Ca2+ signaling pathway in cancer, along with the associated challenges.

The innate immune response to bone biomaterials critically regulates osteogenesis, yet the molecular mechanisms governing neutrophil-macrophage crosstalk remain poorly understood. Building on our discovery of neutrophil involvement in bone regeneration, we investigated the E3 ubiquitin ligase-Tripartite motif containing protein 30a (TRIM30a) as a potential orchestrator of inflammatory resolution and osseointegration. Through integrated multi-omics analysis of pro-osteogenic versus non-osteogenic metallic implants, we identified TRIM30a as a key regulator. Using conditional knockout mice (whole-body, neutrophil-specific, and macrophage-specific TRIM30a deficiency) combined with NETosis assays and inflammatory signaling profiling, we systematically evaluated TRIM30a's role on NETosis/cGAS-STING axis in bone regeneration, with pharmacological validation using DNase I in murine tibial implant models. TRIM30a expression was positively correlated with the osteogenic ability of pro-osteogenic implants. Mechanistically, TRIM30a suppressed NF-κB/NLRP3 signaling in neutrophils, while synergizing with NET-derived dsDNA to modulate cGAS-STING signaling in macrophages, thereby achieving balanced cytokine production. Therapeutic intervention with DNase I rescued bone formation in TRIM30a-deficient mice, confirming the clinical relevance of this pathway. Our work establishes TRIM30a as a master regulator of bone regeneration through dual mechanisms: restraining neutrophil hyperactivation via NF-κB/NLRP3 inhibition while cooperating with dsDNA to calibrate macrophage cGAS-STING signaling, revealing a targetable immunomodulatory axis for enhancing osseointegration. These findings provide new insights into the immune-bone regeneration interface and suggest novel therapeutic strategies for implant-related bone repair.

Background Tumor-associated macrophages (TAMs) are among the most prevalent cells within the tumor microenvironment (TME) of cervical cancer (CC). Although TAMs frequently exhibit an immunosuppressive phenotype, their plasticity enables them as an intriguing reprogrammable target for immunotherapy of CC.Methods Consensus clustering was employed to delineate immune infiltration patterns in a cohort of 119 patients with CC. Single-cell RNA sequencing, complemented by flow cytometry analysis, was used to characterize hexokinase 3 (HK3)-expressing cell populations. In vivo tumor models were established to assess the functional impact of HK3-expressing cells on the TME, with interventions including Hk3 knockout and CD8+ T-cell depletion. A comprehensive approach involving bulk RNA sequencing, immunoprecipitation assays, confocal microscopy imaging, and in vitro co-culture systems was implemented to elucidate the mechanisms underlying HK3 inhibition-mediated enhancement of antitumor immunity. Furthermore, the therapeutic efficacy of HK3 inhibition, both as a monotherapy and in combination with immunotherapeutic strategies, was systematically evaluated in preclinical tumor models.Results We elucidated a cross-regulation between TAMs and CD8+ T cells, with HK3 serving as a central regulatory node. Upon HK3 expression was upregulated by CD8+ T cells through the IFN-γ-STAT1 signaling axis, TAMs exhibited impaired cross-presentation capacity, which in turn attenuated CD8+ T cell-mediated antitumor immunity. Mechanistically, HK3 physically interacted with mechanistic target of rapamycin (mTOR), promoting nuclear translocation of transcription factor EB (TFEB) and resulting in excessive lysosomal activation and antigen degradation. Moreover, targeting HK3 in combination with immune checkpoint blockade yielded a synergistic effect in enhancing antitumor immunity.Conclusions Targeting HK3 in TAMs represents a promising therapeutic strategy capable of enhancing antitumor immunity and synergizing with immune checkpoint blockade by restoring efficient antigen cross-presentation.