Background: N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity. Methods: Bladder cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate Cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan–Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated. Results: Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan–Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib. Conclusions: An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.

Aberrant expression of circular RNAs (circRNAs) has been reported to play an important biological regulatory role in gastric cancer (GC). For the purpose of silencing cancer‐related genes, a new approach for cancer treatment using nanocarriers to deliver siRNA has been proposed. In this study, abundantly expressed circMAP2K2 (hsa_circRNA_102415) is identified in GC cells. CircMAP2K2 regulates the PCBP1/GPX1 axis through proteasome‐mediated degradation, which further mediates the activation of the AKT/GSK3β/epithelial‐to‐mesenchymal transition (EMT) signaling pathway and enhances the proliferation and metastatic ability of GC cells. To establish novel GC treatment, epigallocatechin‐3‐gallate‐lysozyme (EGCG‐LYS) fibrils are synthesized, and in vitro experiments demonstrate that EGCG‐LYS has a higher siRNA delivery efficiency than Lipofectamine 2000 (lipo2000), which effectively silences the expression of circMAP2K2. Further studies show that EGCG‐LYS carrying siRNA can successfully achieve lysosome escape, which allows it to be located in the cytoplasm to achieve post‐transcriptional gene silencing. In addition, EGCG‐LYS carrying si‐circMAP2K2 has good circulating stability, excellent biosafety and antitumor ability in vivo. The EGCG‐LYS fibrils delivery system provides a new tool and approach for the treatment of GC.

The incidence of urothelial carcinoma (UC) ranks second among all urological cancers, accounting for over 90% of malignant tumors in bladder. Patients diagnosed with UC experience a lower quality of life due to rapid progression of the disease. Early and non-invasive detection is curial for diagnosing UC and improving patient outcomes. This study aimed to develop and validate a DNA methylation assay for the early detection and monitoring for UC, with a focus on its diagnostic and prognostic implications. The DNA methylation assay with real-time methylation specific polymerase chain reaction (RT-MSP) technique measures the methylation level of SOX1-OT and HIST1H4F in urine samples. A cohort comprising 436 patients diagnosed with UC or other urologic disease as well as 79 healthy patients was retrospectively utilized to evaluate this assay. Furthermore, UC patients who underwent surgery are included to assess its ability to detect recurrence. The DNA methylation assay demonstrated significantly increased methylation level in tumor tissues and a high positive rate in urine samples from UC patients. The methylation profile effectively distinguishes UC from other non-UC urologic disease, exhibiting a high sensitivity (85.2%) and specificity (90.0%) for UC diagnosis. Furthermore, the assay showed promising ability in differentiating UC patients based on tumor grade, malignancy potential, and disease stage. Additionally, the DNA methylation assay demonstrated a superior ability to detect UC recurrence with a high area under curve (AUC) of 0.979. This research proposes a novel DNA methylation assay with urine as sample for detection, representing a cost-efficient and non-invasive method for diagnosing and monitoring UC disease.

Background: Therapeutic resistance limits durable survival in advanced/metastatic renal cell carcinoma (RCC) treated with first‐line tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI). We sought to define key resistance drivers and actionable targets. Methods: Integrated RNA sequencing of cabozantinib‐resistant RCC cells, lipid metabolomics, and PD‐L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK‐8, and colony formation assays in vitro and by nude‐mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell–T‐cell co‐culture assays were used to dissect ENPP2‐dependent CD8+ T‐cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI–ICI regimens was tested in RCC patient‐derived xenograft models. Results: The ATX–LPA axis conferred TKI resistance via constitutive AKT/mTOR activation and promoted immune evasion by upregulating PD‐L1 through TBK1/IRF3 signaling, thereby impairing intratumoral CD8+ T‐cell function. ENPP2 enhanced PD‐L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI–ICI therapy in preclinical models. Conclusions: Targeting the ATX–LPA axis represents a promising strategy to overcome resistance to current TKI–ICI combinations.