BACKGROUND:Persistent high-risk HPV infections (e.g., HPV16/18/52) are directly linked to cervical cancer development, thus necessitating the development of effective multi-target therapeutic vaccines. METHODS:We developed KDTV001, a non-replicating adenovirus 5-vectored trivalent vaccine encoding engineered E6/E7 oncoproteins from HPV16/18/52. Its immunogenicity was evaluated in C57BL/6, CD1, HLA-transgenic mice, SD rats, and a human DC-T cell co-culture system. Assessments included IFN-γ ELISpot, flow cytometry, tumour challenge/rechallenge, single-cell RNA/TCR sequencing (scRNA/TCR-seq) of lymphocytes, and immune cell depletion. FINDINGS:KDTV001 demonstrated robust preclinical efficacy across multiple models, eliciting potent immune and cross-reactive responses in immunocompetent and HLA-transgenic mice. scRNA/TCR-seq revealed KDTV001 remodelled the tumour microenvironment, increasing cytotoxic CD8+ T cells and promoting T cell clonal expansion and differentiation. A single dose induced complete TC-1 tumour regression in 60-80% of mice with durable protection (>200 days). Optimising the booster immunisation schedule mitigated the impact of pre-existing vector immunity on the immunogenicity of KDTV001. Human relevance was confirmed through antigen-specific T-cell activation and expansion in HLA-A transgenic mice and PBMC co-cultures. INTERPRETATION:KDTV001, the adenovirus 5-vectored trivalent therapeutic vaccine targeting HPV16/18/52, demonstrates potent immunogenicity, significant antitumour efficacy, and long-term protective immunity across diverse preclinical models, paving the way for clinical translation in treating HPV-associated malignancies. FUNDING:This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (Nos.2025ZD0544101), the Hubei Provincial Science and Technology Major Project of China (Nos.2023BCA004), and the National Clinical Research Center for Gynaecological Diseases Special Fund of China (Nos.2025LCPT01).

Microplastics (MPs) have been increasingly detected in human tissues. However, their presence in the female reproductive system remains largely unexplored. In this study, micro-Raman spectroscopy was employed to analyze 60 human uterine tissue samples, including those from patients with uterine fibroids, endometrial cancer, cervical cancer, and healthy controls. MPs were detected in 91.1 % of diseased uterine tissue samples, with a mean abundance of 3.0 +/- 1.53 particles per gram after blank correction. A total of fifteen polymer types were identified, predominantly polyethylene (18.0 %), polypropylene (12.9 %), and polystyrene (8.6 %). Most particles measured less than 30 mu m in length and width. High similarity was observed in MP particle abundance, polymer composition, and size distribution across different types of diseased uterine tissues (p < 0.01). Notably, the mean MP abundance in diseased tissues exceeded that in healthy uterine tissues (1.53 +/- 1.09 particles per gram). Furthermore, MP abundance in diseased samples showed associations with patient age and body mass index. These findings provide evidence of widespread MP accumulation in human uterine tissues and reveal distinct differences between diseased and healthy states. This study offers novel insights into environmental MP exposure within the female reproductive system.

Immunoglobulins (Igs) have traditionally been recognized for their role in antibody production by B cells. However, their expression in cancer cells and their contributions to tumorigenesis and disease progression remain poorly understood. In this study, using single-cell resolution analysis, we identified a distinct subset of tumor cells with high immunoglobulin gene expression, particularly IGKC, which was significantly enriched in metastatic tumors. The overexpression of IGKC in metastatic tumors was further validated by in situ hybridization across multiple types of clinical tumor samples. Integrated analyses of whole-genome and transcriptome sequencing from pan-cancer cell lines in the CCLE revealed that, beyond B‑cell lymphomas, a subset of tumor cells from most carcinoma types also overexpress IGKC. Unlike in the B‑cell lineage, IGKC expression in tumor cells is driven by alternative splicing, generating fusion transcripts rather than the conventional DNA rearrangements seen in B cells. CUT&Tag and RNA sequencing demonstrated that IGKC transcription is directly regulated by TFAP2C, a transcription factor highly expressed in tumors and associated with poor prognosis. Mechanistically, IGKC interacts with hnRNPM, reducing the accumulation of double-stranded RNA, suppressing interferon responses, and ultimately promoting metastatic progression. In vivo, IGKC overexpression markedly accelerated tumor progression in multiple mouse models. Together, these findings identify tumor-derived IGKC as a key driver of metastasis and highlight the TFAP2C–IGKC–hnRNPM axis as a promising target for prognostic assessment and therapeutic intervention in metastatic cancer.

Human papillomavirus (HPV)-associated cervical diseases pose significant health risks to women worldwide. Current clinical interventions face challenges in achieving complete viral clearance and controlling disease progression, with limited efficacy and recurrence risks. To address this unmet need, we developed an innovative nanovaccine (HM-NPs@LP) designed to codeliver tumor cell membranes (TMs), bacterial cytoplasmic membranes (EMs), and HPV16 long peptides (LP) through PLGA nanoparticles to elicit antitumor immunity. HPV16 E5/E6/E7 LP and TM provide individualized broad-spectrum antigen repertoires, including tumor-specific and tumor-associated antigens. EMs serve as natural adjuvants to enhance immunogenicity. The resulting nanovaccine demonstrates uniform nanoparticles (177 nm) with excellent stability and biosafety. In vitro, HM-NPs@LP exhibited efficient uptake by bone marrow-derived dendritic cells (BMDCs), which in turn promoted DC maturation and strengthened tumor-specific T-cell responses. In vivo studies in murine models demonstrate that HM-NPs@LP preferentially accumulate in lymph nodes and elicit potent tumor suppression. Furthermore, this vaccination induces durable immune memory to prevent tumor recurrence with minimal systemic toxicity. Additionally, humanized HLA-A*02:01 transgenic mice mirror these therapeutic outcomes. Synergy with taxane-platinum (TP) chemotherapy and anti-PD-1 immunotherapy further augments tumor regression. Overall, the scalable production, biosafety, and adaptability for personalized immunotherapy position this nanovaccine platform as a promising therapeutic strategy for the treatment of HPV-related cervical diseases and potentially other malignancies.

Pyroptosis is a form of programmed cell death (PCD) that triggers inflammation. Pyroptosis is activated by specific inflammasomes and caspases, leading to the cleavage of gasdermin protein families, especially gasdermin D (GSDMD) and gasdermin E (GSDME). While pyroptosis has been extensively linked to innate immunity and diseases, such as atherosclerosis, the role in cancer remains an area of active investigation. Studies have suggested that pyroptosis influences tumor behavior, including proliferation and invasion, across different tissue types and genetic backgrounds. This process occurs through both canonical and non-canonical pathways involving GSDMD and GSDME. Tumors tend to thrive in the chronic inflammatory environment created by pyroptosis but tumors are more likely to be eradicated if pyroptosis occurs suddenly and extensively. Indeed, targeting pyroptosis pathways holds promise as an anticancer strategy. To date, several drugs are found to have the ability of inducing pyroptosis to enhance tumor clearance. Moreover, pyroptosis-related genes (PRGs) have emerged as valuable biomarkers for prognosis and monitoring the tumor microenvironment (TME). This review explores the mechanisms underlying endogenous and exogenous pyroptosis in cancer, examines the dual role within tumors, discusses the potential for targeting pyroptosis in cancer treatment and prognosis, and highlights the interactions between pyroptosis and other forms of PCD in cancer.

IntroductionThe stimulator of interferon genes (STING) is a central mediator of innate immune sensing and represents a critical regulator of chronic inflammation. Upon persistent infection, excessive neutrophil activation leads to the formation of neutrophil extracellular traps (NETs) that damage the tissues. However, the mechanism by which STING signaling regulates NETs formation under chronic inflammatory conditions remains poorly understood.MethodsIn this study, using LPS-induced murine endometritis models in wild-type and STING-deficient mice, we demonstrated that STING deficiency significantly suppressed myeloperoxidase activity, and diminished NETs formation.ResultsWe identified neutrophil surface molecular CD11b as a key downstream target of STING, whose expression was transcriptionally regulated via IRF7. Furthermore, the STING-IRF7 axis was found to drive lipocalin-2 (LCN2) expression, which acted through its receptor MC4R to upregulate intracellular adhesion molecule-1 (ICAM-1), thereby facilitating neutrophil recruitment and NETosis during LPS stimulation. The role of this pathway was validated both in vitro using isolated neutrophils and in vivo using Lcn2-/- mice. Moreover, STING deficiency reprogramed the endometrial immune microenvironment by reducing inflammatory infiltration and restoring receptivity transcription factor homeobox A10 (HOXA10).DiscussionOur findings revealed a novel mechanism in which the STING-IRF7 pathway exacerbated endometrial inflammation and tissue damage by coordinately upregulating CD11b and activating the LCN2-ICAM-1 axis. Consequently, targeting the STING signaling pathway may offer a promising therapeutic strategy for chronic endometritis.

Cancer-associated fibroblasts (CAFs) are central architects of immunosuppression and therapy resistance across malignancies, yet how tumor-intrinsic genomic instability instructs stromal reprogramming remains unresolved. Integrated single-cell transcriptomics and epigenomics of samples from patients with high-grade serous ovarian carcinoma revealed POSTN+ myofibroblast-like cancer-associated fibroblasts (myCAFs) and effector regulatory T cells (eTreg cells) as critical mediators of immunosuppression in tumors with high genomic instability. Mechanistically, unstable genomes activated tumor-intrinsic STING signaling, triggering WNT3a/7a secretion. WNT/β-catenin signaling in fibroblasts established a POSTN-dependent positive feedback loop that epigenetically locked cells into a POSTN+ myCAF lineage. These myCAFs reciprocally expanded eTreg cells and exhausted CD8+ T cells, thereby converting genomic instability-driven immune activation into suppression and limiting poly(ADP-ribose) polymerase inhibitor (PARPi) efficacy. Therapeutic POSTN blockade reinvigorated T cell cytotoxicity, depleted eTreg cells, and potentiated PARP inhibition in ovarian and breast cancer models, overcoming resistance. Our work resolves the dual roles of genomic instability and identifies POSTN as a stromal-specific checkpoint to mediate immunosuppression in genomically unstable tumors.

[This corrects the article DOI: 10.3389/fimmu.2025.1671848.].

OBJECTIVE To compare the diagnostic accuracy of minipad collected menstrual blood versus clinician collected cervical samples to test for human papillomavirus (HPV) in the detection of cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/CIN3+). DESIGN Cross sectional population based study. SETTING Four urban and three rural communities in Hubei Province, China. PARTICIPANTS 3068 women aged 20-54 years with regular menstrual cycles, enrolled between September 2021 and January 2025. INTERVENTIONS HPVtesting using minipad collected menstrual blood, clinician collected cervical samples, and ThinPrep cytology. Women who tested HPV positive by either collection method or by cytology (atypical squamous cells of undetermined significance or worse) were referred for colposcopy directed biopsy sampling. MAIN OUTCOME MEASURE Diagnostic accuracy for detecting CIN2+ and CIN3+. RESULTS Among 3068 participants, minipad based HPV testing showed a sensitivity of 94.7% (95% confidence interval 80.9% to 99.1%) for CIN2+ detection, comparable to clinician based HPV testing (92.1%, 77.5% to 97.9%; P=1.00). Although minipad HPV testing showed a lower specificity than clinician HPV testing (89.1%, 88.0% to 90.2% v 90.0%, 88.9% to 91.1%; P=0.001), the negative predictive value matched that of clinician HPV testing (99.9%, 99.7% to 100.0% v 99.9%, 99.7% to 100.0%; P=1.00). Both collection methods had a similar positive predictive value (9.9%, 7.1% to 13.5% v 10.4%, 7.4% to 14.3%; P=0.82) and screening efficiency (10.1 v 9.6 referrals per CIN2+ detected; P=0.82). CONCLUSIONS Minipad collected menstrual blood showed comparable diagnostic accuracy to clinician collected cervical samples for HPV testing for detecting CIN2+ and CIN3+. TRIAL REGISTRATION ClinicalTrials.gov NCT06082765.

The indications for Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy in platinum-sensitive recurrent ovarian cancer (PSROC) patients varies across nations. The lack of clinical trial evidence and detailed biomarker analysis in the Asian population results in uncertain clinical benefits. Additionally, the absence of long-term safety monitoring data limits the assessment of tolerance to prolonged PARP inhibitor use. This prospective, open-label, single-arm, phase IIIb L-MOCA study enrolled Asian patients with high-grade epithelial PSROC across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. The primary endpoint of progression-free survival has been reported previously. A prespecified final OS analysis was conducted at approximately 60

This study aims to uncover the role and mechanism of transforming growth factor α (TGFA) on the malignant progression of cervical cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to examine the expression levels of TGFA in cancer cells and tissues. Changes in cell viability, apoptosis, and malignant metastatic ability of cancer cells were detected using methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, and Transwell method respectively. Autophagy was evaluated via microtubule-associated proteins light chain 3 (LC3) and sequestosome 1 (p62) expression. A nude mouse xenograft model was used for in vivo validation. RNA pull-down assay was performed to explore the interaction between TGFA and desmoglein 2 (DSG2). These results indicated that TGFA expression was elevated in both cervical cancer tissues and cells. TGFA overexpression promoted cell proliferation, metastasis, and autophagy, whereas TGFA knockdown exerted the opposite effects and inhibited tumor growth. Mechanistically, TGFA bound to DSG2 and affected the downstream MYC oncogene (c-MYC)/ADAM metallopeptidase domain 17 (ADAM17) pathway. In conclusion, TGFA serves as an upstream regulator of the DSG2/c-MYC/ADAM17 axis, which is correlated with autophagy and malignant progression of cervical cancer.

Cervical cancer, especially cervical squamous cell carcinoma (CSCC), is a major public health issue in low- and middle-income countries, with advanced recurrence and metastasis linked to poor prognosis. It shows significant intra-tumoral phenotypic heterogeneity and plasticity. We analyzed the single-cell RNA sequencing data of cervical squamous cell carcinoma available in the Gene Expression Database (GEO) and identified the tumor cell subtype exhibiting hypoxic characteristics. We extracted differentially expressed genes (HRDEGs) between this hypoxia-related cluster and other tumor cells. Based on the CSCC bulk RNA sequencing data from the Cancer Genome Atlas (TCGA), this subtype was confirmed to be closely associated with poor prognosis in CSCC.101 combinations consisting of 10 machine learning models were used for screening prognostic biomarkers in HRDEGs, and a hypoxia signature was established by multivariate COX regression. The hypoxia signature, validated using external GEO datasets, was significantly correlated with tumor invasiveness. Further analysis demonstrated that immune infiltration and responses to both chemotherapy and immunotherapy are associated with the hypoxia signature. In addition, the key gene P4HA2 in the hypoxia signature has been demonstrated to be involved in the regulation of malignant phenotypes of tumor cells and the regulation of HIF-1α stability. Overall, this hypoxia signature is a promising independent prognostic factor, provides potential biomarkers for the prognosis of CSCC and may guide future investigations into patient stratification.

Cervical cancer progresses from high-grade squamous intraepithelial lesions driven by persistent HPV infection. Identifying the gatekeepers restraining malignant transformation could reveal strategies to prevent and treat cervical cancer. Here, we integrated single-cell transcriptomics, CRISPR-Cas9 screening, and organoid modeling to dissect this process. Single-cell analysis of patient samples revealed progressive activation of RAS and proliferation programs along epithelial differentiation paths. A focused CRISPR screen in HPV-positive pre-tumoroids identified NF1 as the top suppressor of malignant transition. NF1 loss accelerated carcinogenesis in organoids, compressing a 5~10-year process into 3~6 months, recapitulating basal cell expansion, dedifferentiation, and tumorigenicity. Mechanistically, NF1 loss enhanced RAS-MAPK and PI3K-AKT signaling, promoted proliferative programs, and remodeled chromatin accessibility at AP-1/E2F motifs. Conversely, NF1 restoration in cancer organoids induced apoptosis and suppressed malignant maintenance. AI-guided modeling was used to design a minimal NF1-mimetic peptide that engaged RAS-GTP to inhibit RAS signaling, reduce tumor burden in HPV16-driven mouse models, and restore local immune permissiveness without systemic activation. Together, these findings establish NF1 as a critical constraint on HPV-associated epithelial evolution and provide a time-compressed organoid model of cervical carcinogenesis, offering proof-of-concept for therapeutic RAS pathway interception via NF1 restoration.

This study aimed to investigate the association between human papillomavirus (HPV) 16/18, HPV integration status, and cervical intraepithelial neoplasia grade 3 or worse (CIN3 +), and to provide evidence and theoretical support for the clinical translation of HPV integration testing. This was a multicenter cross-sectional study conducted within a cervical cancer screening program in China. HPV integration was detected using high-throughput viral integration detection (HIVID). Structural equation modeling (SEM) was employed to examine the mediating effect of HPV integration. A total of 3,077 high-risk HPV-positive women were included in the final analysis. Among these participants, 29.5