The choice of chemo- or immuno-therapy for muscle-invasive bladder cancer (MIBC) patients remains contentious. Podoplanin is newly identified as an immune checkpoint which intrigues us to explore the clinical significance and immunoregulatory role of tumor-infiltrating podoplanin⁺ cells (PDPN⁺ cells) in MIBC. A retrospective analysis of 259 MIBC patients from Zhongshan Hospital (n = 141) and Shanghai Cancer Center (n = 118) was conducted. A total of 406 MIBC patients from TCGA database were enrolled to investigate the relationship between PDPN and molecular characterization. We found that tumor-infiltrating PDPN⁺ cell abundance indicated an inferior overall survival and recurrence-free survival. pT2 MIBC patients with PDPN⁺ cell low infiltration could benefit more from adjuvant chemotherapy (ACT). Increased PDPN⁺ cell infiltration was associated with diminished GZMB and TNF-α expression while correlated with expanded PD-1, PD-L1, LAG-3 and TIM-3 expression and tumor-promoting regulatory T cell and M2 macrophage infiltration. Tumors with high PDPN mRNA expression mainly presented luminal-infiltrated and basal-squamous subtypes (2017 TCGA classification) or stroma-rich and Ba/Sq subtypes (consensus classification). Elevated PDPN mRNA expression was associated with less FGFR3 activation signature and more T-cell-inflamed signature and EGFR activation signature. In conclusion, tumor-infiltrating PDPN⁺ cells could be applied as an independent prognosticator for clinical outcome and a predictive biomarker for suboptimal ACT responsiveness, which was also associated with immunosuppressive contexture infiltration. Intratumoral PDPN expression had a correlation with MIBC molecular classification and therapy-related signatures. The novel immune checkpoint PDPN should be considered as a possible immunotherapeutic target for MIBC.

Immunoglobulin G4–related disease (IgG4-RD) is a new clinical entity. Characteristic features of IgG4-RD are elevated serum IgG4 levels, infiltration of IgG4-positive cells, mass-forming lesions with fibrosis and good response to corticosteroids. The variable imaging features of IgG4-RD and the overlap with other differential diagnoses often pose a diagnostic challenge, as they frequently mimic malignant tumors or other inflammatory diseases in the abdomen.

Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous noncoding RNAs in the nucleoplasm. Here we find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels. Specifically, ZCCHC8 depletion results in significant upregulation of nascent long noncoding RNAs (lncRNAs) containing G-quadruplex (G4) and U-Rich motifs (G4/U-Rich lncRNAs). The G4 motif binds to EZH2, blocking the chromatin recruitment of PRC2, while the U-Rich motif is specifically recognized by the NEXT complex for RNA exosome-mediated degradation. In tumor tissues with high ZCCHC8 expression in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patients, the NEXT complex excessively degrades nascent G4/U-Rich lncRNAs. Consequently, PRC2 core subunits are released and recruited to neighboring genomic loci, resulting in increased H3K27me3 levels and downregulation of adjacent genes, including tumor suppressors like SEMA5A and ARID1A. Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading nascent G4/U-Rich lncRNAs in cancer cells.

During the postoperative management of urinary diseases, oral or intravenous administration of drugs and implanting ureteral stents are usually required, making localized drug delivery by ureteral stent a precise and effective medication strategy. In the traditional drug loading method, the drug was premixed in the implants in production lines and the versatility of drugs was restricted. However, the complex situation in the urinary system fails the possibility of finding a “one fits all” medication plan, and the intraoperative drug-loading of implants is highly desired to support customized therapy. Here, we designed an ultrathin (8 μm), elastic, and self-adhesive nanofiber bio-tape (NFBT) that can easily encapsulate drugs on the stent surface for controllable localized drug delivery. The NFBT exhibited high binding strength to a ureteral stent, a sustained release over 7 d in PBS for hydrophilic drug, and a zero-order release curve over 28 days for the hydrophobic drug nitrofurantoin (NFT). Further in vivo experiments using a porcine ureteral tract infection model demonstrated that NFBT loaded with NFT could significantly reduce the bacterial concentration in urine. The total amount of NFT delivered by the NFBT was about 2.68 wt% of the recommended dose for the systemic administration.