Platinum resistance remains a major obstacle in ovarian cancer, yet whether abnormal glycolysis and lactate metabolism drive this phenotype through protein lactylation remains unclear. Here, we investigated the role of lactate-driven protein lactylation in platinum resistance and sought to identify the key effector event involved. Global protein lactylation was assessed by immunohistochemistry in tumor samples from 122 patients with high-grade serous ovarian cancer, and integrated proteomic and lactylomic analyses were performed in fresh frozen tumors from 12 patients, followed by validation in ovarian cancer cell models and functional assays. Platinum resistant ovarian cancer exhibited enhanced glycolysis, increased lactate accumulation, and elevated global protein lactylation, which was associated with platinum resistance and shorter progression free survival. Integrated lactylome profiling identified ZMYM2 K529 lactylation as a platinum resistance associated event, and ZMYM2 was upregulated in platinum resistant tissues and cells. Mechanistically, lactate promoted ZMYM2 K529 lactylation, suppressed ubiquitin-proteasome mediated degradation, and increased ZMYM2 stability and abundance. Functionally, ZMYM2 enhanced cisplatin tolerance, homologous recombination repair, and tolerance to DNA damaging treatments. However, both wild-type ZMYM2 and the K529R mutant restored platinum-resistant phenotypes in ZMYM2-knockdown cells, indicating that K529 lactylation primarily maintains ZMYM2 stability rather than directly determining its downstream pro-resistance activity. Collectively, these findings identify a glycolysis-lactate-ZMYM2 lactylation axis that promotes platinum resistance in ovarian cancer and highlight lactylation-dependent ZMYM2 stabilization as a potential therapeutic vulnerability.

Background/Objectives: Ovarian cancer has the highest mortality among gynecological malignancies, with platinum resistance significantly contributing to poor prognosis. We aimed to develop a multimodal model (MMHC-OCPR) to predict platinum response and recurrence risk, enabling earlier personalized treatment and improved outcomes. Methods: This multicenter retrospective study included a combined cohort of 431 patients, comprising 1182 whole slide images (WSIs) curated from two independent datasets. The primary cohort consisted of 376 patients from the National Cancer Center (China), which was further partitioned into training, validation and internal test sets to ensure model development and evaluation. An additional external test cohort was incorporated using publicly available data from TCGA, enhancing the generalizability of our findings. We implemented a weakly supervised multiple instance learning framework to integrate histopathological imaging with clinicopathological variables, further strengthened by the incorporation of the transformer-based pretrained encoder UNI2-h, which enhanced the model's predictive performance. Results: All patients in the primary cohort had pathology slides collected from primary ovarian tumors and metastatic tumor, along with clinical factors related to prognosis and treatment response. The baseline platinum response classifier using primary WSIs achieved an AUC of 0.896 in the internal test group and 0.876 in the external test group. Integration of metastatic WSIs and clinical data inputs yielded a superior AUC of 0.914 in the internal test set. The recurrence risk model demonstrated a C-index of 0.801, rising to 0.838 after multimodal enhancement. The model stratified patients into low-, intermediate- and high-risk groups with 2-year progression-free survival rates of 77.3%, 48.0% and 2.0%, respectively. Conclusions: Our model enables the early detection of platinum resistance, guiding timely treatment intensification. The recurrence risk stratification supports personalized management by identifying patients with favorable outcomes following surgery and chemotherapy, potentially sparing them from maintenance therapy to reduce associated toxicity, cost, and enhance quality of life.

Background:Ovarian cancer (OC), characterized by a high mortality rate and limited treatment options, underscores the urgent need to identify novel therapeutic targets to advance individualized precision therapy. Exploring the potential of antidiabetic drug target genes as therapeutic candidates may expand the treatment repertoire of diverse OC subtypes. Methods:Leveraging datasets involving the Ovarian Cancer Association Consortium, the eQTLGen consortium, and the Genotype-Tissue Expression database, we implemented an integrated analytical framework combining two-sample Mendelian randomization (MR), summary data-based MR, as well as colocalization analysis to assess the association between target genes of antidiabetic drugs with the risk and survival of different ovarian cancer subtypes. Positive control analysis, replication analysis, MR-Egger regression, Bonferroni correction, and MR-PRESSO outlier test were employed to further validate the robustness of the associations. Results:We systematically analyzed the associations of nine OC phenotypes with the target genes from nine antidiabetic drugs, including sulfonylureas, metformin, alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZDs), dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 analogues (GLP-1A), insulin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other drugs. Notably, multiple target genes showed consistent and significant associations with specific OC risk: AKR1A1 with Low grade serous OC; HMGCR and KCNJ11 with clear cell OC; ITGAL and AKR1B1 with mucinous OC; and AKR1A1 and ITGAL with endometrioid OC. Although high grade serous OC risk was linked to certain genes in only one method, its survival was associated with DPP4 in two approaches. Conclusion:This study reveals marked subtype-specific heterogeneity in the genetic relationships between antidiabetic targets and ovarian cancer (OC), pointing to a direction for future translational research into drug repurposing for subtype-specific applications. These findings support a metabolic basis in OC progression and may inform the development of tailored therapeutic strategies based on pathological subtypes.

Background:While surgery and radiotherapy remain primary treatments for HPV-associated vulvar/vaginal squamous cell carcinoma (SCC), the significant complications and impaired quality of life underscore the need for alternative approaches. We report two cases achieving pathological complete response (pCR) with neoadjuvant chemoimmunotherapy. Cases:Two biopsy-confirmed HPV-associated vulvar/vaginal SCC cases with inguinal lymph node metastases (both PD-L1 CPS < 1) received three cycles of neoadjuvant camrelizumab plus nab-paclitaxel/cisplatin. Subsequent imaging demonstrated marked tumor regression, permitting urethra-preserving resection. Histopathological analysis confirmed pCR, with no recurrence at 6-month follow-up. Conclusion:Neoadjuvant chemoimmunotherapy may be an effective treatment for HPV-associated vulvar/vaginal SCC, potentially independent of PD-L1 CPS status, while improving post-treatment quality of life compared to conventional therapies.

Ovarian cancer therapy remains limited by high recurrence and unsatisfactory responses to current treatments. Here, we developed a multifunctional nanoplatform (CuS@Vk3@LA) that integrates photothermal therapy (PTT), chemodynamic therapy (CDT), and near-infrared (NIR)-controlled drug release. The hollow CuS core serves as both a NIR absorber and a Fenton-like catalyst, enabling simultaneous heat generation and hydroxyl radical production. Uniquely, vitamin K3 (Vk3) was incorporated to enhance endogenous H₂O₂ levels through NQO1-mediated redox cycling, thereby overcoming the substrate shortage that restricts conventional CDT. To prevent premature leakage, lauric acid (LA) was introduced as a thermosensitive phase-change shell, which melts under mild hyperthermia to trigger on-demand release. This rational design establishes a dual oxidative-stress mechanism-ROS amplification and GSH depletion-resulting in synergistic tumor cell killing. Systematic evaluations demonstrated excellent colloidal stability, biocompatibility, and tumor-selective accumulation. In vivo, CuS@Vk3@LA achieved pronounced tumor growth inhibition with minimal systemic toxicity. Collectively, this study provides a precise and safe nanotherapeutic strategy that combines catalytic amplification with photothermal activation, showing strong translational potential for ovarian cancer treatment.

OBJECTIVE:This study aimed to investigate the impact of adjuvant external beam radiotherapy (EBRT) following initial surgery on the efficacy of immunotherapy in patients with recurrent endometrial cancer. METHODS:This is a single-institution retrospective cohort study. Patients who underwent initial surgery for endometrial cancer and received immunotherapy for recurrence between January 2020 and December 2023 were recruited. Patients who received post-operative EBRT were assigned to the EBRT group. Patients who did not undergo EBRT or who received brachytherapy without EBRT were assigned to the control group. Progression-free survival was used as the end point. Kaplan-Meier curves were used for comparing progression-free survival. The multi-variate analysis was performed using the Cox proportional hazards regression model. RESULTS:A total of 91 patients were included in the analysis; 33 had a history of EBRT, while 58 had not received prior EBRT. In Kaplan-Meier curves, patients who did not receive EBRT showed a numerically lower risk of disease progression (HR 0.47, 95% CI 0.25 to 0.90, p = .010). In multi-variate analysis, EBRT (HR 5.28, 95% CI 1.54 to 22.06) and proficient mismatch repair/micro-satellite instability-low/micro-satellite stable status (HR 3.15, 95% CI 1.19 to 8.90) were risk factors for disease progression during immunotherapy. CONCLUSIONS:In patients with recurrent endometrial cancer who received immunotherapy, the therapeutic efficacy may be compromised by prior post-operative adjuvant EBRT.

BACKGROUND:The impact of examined lymph node (LN) count on survival in cervical cancer remains understudied, with no consensus on the optimal number required. OBJECTIVES:We aimed to investigate the role of LN count in postoperative pathological evaluation for cervical cancer patients undergoing surgery. METHODS:Data from the US SEER database and a retrospective Chinese cohort were analyzed. Multivariable logistic and Cox regression models assessed LN positivity detection and overall survival (OS), respectively. Smoothing spline curves and Chow tests identified structural change points in hazard ratios and LN-positive ratios. RESULTS:Among 14,133 SEER and 2,811 Chinese cases, higher LN counts correlated with increased detection of positive LNs (OR: 1.040, 95% CI: 1.019-1.062) and improved OS (HR: 0.990, 95% CI: 0.984-0.996). Structural change points occurred at 20 LNs for LN-negative patients and 13 LNs for LN-positive patients (both P < 0.001). An elevated LN-positive ratio (positive/examined LNs) strongly predicted worse OS (HR: 4.208; 95% CI: 1.454-12.181). CONCLUSIONS:An increased number of examined LNs significantly contributes to the detection of positive LNs and improved patient survival. For patients with claimed LN-negative and LN-positive disease, a minimum examination of 20 and 13 LNs, respectively, is recommended to ensure adequate LN evaluation. The LN positive ratio is a strong prognostic indicator in patients with LN-positive disease.

Cervical squamous cell carcinoma (CSCC) represents a significant global health concern among females. Identifying new biomarkers and therapeutic targets is pivotal for improving the prognosis of CSCC. This study investigates the prognostic relevance of CCZ1 in CSCC and elucidates its downstream pathways and targets using a combination of bioinformatics analysis and experimental validation. Transcriptomic analysis of 239 CSCC and 3 normal cervical samples from The Cancer Genome Atlas database reveals a marked upregulation of CCZ1 mRNA levels in CSCC, and elevated CCZ1 mRNA levels were associated with poor prognosis. Immunohistochemical analysis of clinical samples also confirmed these findings. Furthermore, functional assays, including Cell Counting Kit-8, colony formation, Transwell, and flow cytometry, elucidated the influence of CCZ1 on CSCC cell proliferation, migration, invasion, and cell cycle progression. Remarkably, CCZ1 knockdown suppressed CSCC progression both in vitro and in vivo. Mechanistically, CCZ1 knockdown downregulated MMP2 and MMP17 expression. Restoring MMP2 or MMP17 expression rescued phenotypic alterations induced by CCZ1 knockdown. Hence, CCZ1 promotes CSCC progression by upregulating MMP2 and MMP17 expression, emerging as a novel biomarker in CSCC and presenting potential as a therapeutic target in CSCC.

PurposeTo explore the effectiveness of the model based on non-negative matrix factorization (NMF), analyze the tumor microenvironment and immune microenvironment for evaluating the prognosis of lung adenocarcinoma, establish a risk model, and screen independent prognostic factors.MethodsDownloading the transcription data files and clinical information files of lung adenocarcinoma from TCGA database and GO database, the R software was used to establish the NMF cluster model, and then the survival analysis between groups, tumor microenvironment analysis, and immune microenvironment analysis was performed according to the NMF cluster result. R software was used to construct prognostic models and calculate risk scores. Survival analysis was used to compare survival differences between different risk score groups.ResultsTwo ICD subgroups were established according to the NMF model. The survival of the ICD low-expression subgroup was better than that of the ICD high-expression subgroup. Univariate COX analysis screened out HSP90AA1, IL1, and NT5E as prognostic genes, and the prognostic model established on this basis has clinical guiding significance.ConclusionThe model based on NMF has the prognostic ability for lung adenocarcinoma, and the prognostic model of ICD-related genes has a certain guiding significance for survival.

在化学药物治疗和靶向药物治疗过程中,少部分细胞可以通过进入缓慢增殖状态来逃避死亡,称为耐药持久性(drug tolerant persister,DTP).这种状态可以使癌细胞在药物治疗过程中存活,而且此状态可逆,在药物作用消失后可再次恢复成增殖状态,从而导致疾病进展或复发.因此,DTP成为癌症治愈的阻碍之一,深入学习了解相关耐药机制具有重要临床意义.本综述通过表观基因组修饰、旁路信号通路激活、肿瘤微环境、抑制细胞凋亡和神经递质等方面对目前DTP机制的研究进展作一综述,讨论现有机制对癌症治疗失败或复发的潜在治疗策略.

Cancer cells tend to obtain the substances needed for their development depending on altering metabolic characteristics. Among the reorganized metabolic pathways, Glutamine pathway, reprogrammed to be involved in the physiological process including energy supply, biosynthesis and redox homeostasis, occupies an irreplaceable role in tumor cells and has become a hot topic in recent years. Lung cancer currently maintains a high morbidity and mortality rate among all types of tumors and has been a health challenge that researchers have longed to overcome. Therefore, this study aimed to clarify the essential role of glutamine pathway played in the metabolism of lung cancer and its potential therapeutic value in the interventions of lung cancer.

BackgroundLung adenocarcinoma (LUAD) has a very high morbidity and mortality rate, and its pathogenesis and treatment are still in the exploratory stage. Fatty acid metabolism plays a significant role in tumorigenesis, progression, and immune regulation. However, the gene expression of fatty acid metabolism in patients with LUAD and its relationship with prognosis remain unclear.MethodsWe collected 309 fatty acid metabolism-related genes, established a LUAD risk model based on The Cancer Genome Atlas (TCGA) using Least Absolute Shrinkage Selection Operator (LASSO) regression analysis, and divided LUAD patients into high-risk and low-risk groups, which were further validated using the Gene Expression Omnibus (GEO) database. The nomogram, principal component analysis (PCA), and receiver operating characteristic (ROC) curves showed that the model had the best predictive performance. The ROC curves and calibration plots confirmed that the nomogram had good predictive power. We further analyzed the differences in clinical characteristics, immune cell infiltration, immune-related functions, chemotherapy drug sensitivity, and immunotherapy efficacy between the high-risk and low-risk groups. We also analyzed the enrichment pathways and protein–protein interaction (PPI) networks of different genes in the high-risk and low-risk groups to screen for target genes and further explored the correlation between target genes and differences in survival prognosis, clinical characteristics, gene mutations, and immune cells.ResultsRisk score and staging are independent prognostic factors for patients with LUAD. The high-risk group had lower immune cell infiltration, was more sensitive to chemotherapeutic agents, and had a poorer survival prognosis. We also obtained three pivotal genes with poor survival prognosis in the high expression group, which were strongly associated with clinical symptoms and immune cells.ConclusionRisk score and staging are independent prognostic factors for patients with LUAD. The high-risk group had lower immune cell infiltration, was more sensitive to chemotherapeutic agents, and had a poorer survival prognosis. We also obtained three survival prognosis-associated target genes that are closely associated with clinical symptoms and immune cells and may be potential targets for immune-targeted therapy in LUAD.

Thymomas and thymic carcinomas are malignant thymic epithelial tumors (TETs) with poor outcomes if non-resectable. However, the tumorigenesis, especially the metabolic mechanisms involved, is poorly studied. Untargeted metabolomics analysis was utilized to screen for differential metabolic profiles between thymic cancerous tissues and adjunct noncancerous tissues. Combined with transcriptomic data, we comprehensively evaluated the metabolic patterns of TETs. Metabolic scores were constructed to quantify the metabolic patterns of individual tumors. Subsequent investigation of distinct clinical outcomes and the immune landscape associated with the metabolic scores was conducted. Two distinct metabolic patterns and differential metabolic scores were identified between TETs, which were enriched in a variety of biological pathways and correlated with clinical outcomes. In particular, a high metabolic score was highly associated with poorer survival outcomes and immunosuppressive status. More importantly, the expression of two prognostic genes (ASNS and BLVRA) identified from differential metabolism-related genes was significantly associated with patient survival and may play a key role in the tumorigenesis of TETs. Our findings suggest that differential metabolic patterns in TETs are relevant to tumorigenesis and clinical outcome. Specific transcriptomic alterations in differential metabolism-related genes may serve as predictive biomarkers of survival outcomes and potential targets for the treatment of patients with TETs.

胸腺上皮性肿瘤是位于前纵膈较为罕见的肿瘤,目前治疗策略以手术治疗为主,复发或无法进行手术的晚期患者仍缺乏有效的治疗方案.近年来靶向治疗、免疫治疗等精准治疗在许多肿瘤中获得可观的成效.本文将综述胸腺上皮性肿瘤主要的差异表达基因及其应用的研究进展,为胸腺上皮性肿瘤的治疗提供新的思路.

Long non-coding RNAs (lncRNAs) are a kind of transcripts which are longer than 200nt and have not protein-coding ability due to the lack of an open reading frame. However, lncRNAs can be involved in tumorigenesis and progression in various ways at the transcriptional and post-transcriptional levels. Bladder cancer associated transcript 1 (BLACAT1) as a lncRNA located on human chromosome 1q32.1, is ectopic expression in various tumors (bladder cancer, gastric malignant tumor, lung carcinoma, et al) and can regulate tumor cell proliferation, anti-apoptosis, invasion and metastasis by different mechanisms leading to occurrence and development of tumors. In this review, we summarized current studies of the functions and mechanisms of BLACAT1 in malignant tumors.

长链非编码RNA在多种人类肿瘤中扮演重要角色.小核仁RNA宿主基因15(small nuclear RNA host gene 15,SNHG15)作为一个新发现的长链非编码RNA,在胃癌、肝癌、胰腺癌等多种人类肿瘤中高表达.异常表达的SNHG15与患者的临床特征密切相关,并通过不同机制调节肿瘤细胞的增殖、抗凋亡、侵袭和转移.SNHG15有可能成为肿瘤诊断和治疗的潜在靶点.本文就SNHG15在肿瘤发生、发展中的作用及潜在分子机制作一综述.

长链非编码RNA(Long non-coding RNA,lncRNA)是一类长度超过200个核苷酸且缺乏开放性阅读框架的非编码RNA,在表观遗传、转录以及转录后等多个水平参与肿瘤的发生发展.lncRNA KCNQ1重叠转录物1(KCNQl opposite strand/antisense transcript 1,KCNQ1OT1)在多种肿瘤中异常表达并在其中起不同的作用.研究KCNQl OT1在不同肿瘤中的作用及相关机制有望为肿瘤治疗提供新的思路.本文对KCNQl OT1在肿瘤中作用的研究进展进行综述.

Long noncoding RNAs (lncRNAs) have been shown to play key roles in various human tumors. Ectopic expression of the lncRNA FEZ finger zinc 1 antisense 1 (FEZF1-AS1) have been reported in different cancers, including colorectal cancer, gastric neoplasia, hepatocellular carcinoma and so on. Summarizing all literature correlated with FEZF1-AS1, it is obvious that FEZF1-AS1 is mainly involved in tumorigenesis and progression through competing endogenous RNA (ceRNA) which sponges tumor-suppressive microRNA (miRNA) and recruiting mechanism. Moreover, the aberrant expression of FEZF1-AS1 is related to clinical features of patients with cancers, and regulates cellular proliferation, anti-apoptosis, invasion and metastasis through diverse underlying mechanisms. The role of FEZF1-AS1 in carcinogenesis and progression suggests that it may be a potential diagnostic biomarker or a novel therapeutic target for cancers.