Background/Objectives: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is known as an enhancer of collagen fiber deposition and cross-linking stability. However, there is limited information on its function in tumors. In this study, we aimed to elucidate the function and potential mechanism of action of PLOD1 across cancers. Methods: We assessed the pan-cancer expression, mutation, methylation and prognostic value of PLOD1 through multiple online databases. In addition, we performed correlation analyses of its immunological features, as well as functional assessment analyses of PLOD1. Finally, we assessed the effect of PLOD1 knockdown on bladder tumor cells using in vitro experiments. Results: Our findings suggest that PLOD1 is aberrantly expressed in multiple cancer types, accompanied by a poor prognosis. Epigenetic alterations in PLOD1 are highly heterogeneous across a wide range of tumors, and aberrant methylation and copy number variants correlate with a poor prognosis. In the tumor microenvironment, PLOD1 expression correlated positively with the infiltration level of various immunosuppressive cells (e.g., monocytes, macrophages and tumor-associated fibroblasts) and negatively with immune-killing cells (e.g., CD8⁺ T cells, B cells and CD4⁺ T cells). In addition, PLOD1 expression was associated with immune checkpoints and immunomodulatory genes. Finally, in vitro experiments demonstrated that knockdown of PLOD1 reduced the proliferation, migration and antiapoptotic abilities of T24 cells. Conclusions: The results of this study demonstrate that PLOD1 is a potential oncogene and prognostic biomarker in pan-cancer; tumor tissues with high PLOD1 expression reveal a relatively immunosuppressive tumor microenvironment.

Objectives: Accurate survival predictions and early interventional therapy are crucial for people with clear cell renal cell carcinoma (ccRCC). Methods: In this retrospective study, we identified differentially expressed immune-related (DE-IRGs) and oncogenic (DE-OGs) genes from The Cancer Genome Atlas (TCGA) dataset to construct a prognostic risk model using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. We compared the immunogenomic characterization between the high- and low-risk patients in the TCGA and the PUCH cohort, including the immune cell infiltration level, immune score, immune checkpoint, and T-effector cell- and interferon (IFN)-γ-related gene expression. Results: A prognostic risk model was constructed based on 9 DE-IRGs and 3 DE-OGs and validated in the training and testing TCGA datasets. The high-risk group exhibited significantly poor overall survival compared with the low-risk group in the training ( P < 0.0001), testing ( P = 0.016), and total ( P < 0.0001) datasets. The prognostic risk model provided accurate predictive value for ccRCC prognosis in all datasets. Decision curve analysis revealed that the nomogram showed the best net benefit for the 1-, 3-, and 5-year risk predictions. Immunogenomic analyses of the TCGA and PUCH cohorts showed higher immune cell infiltration levels, immune scores, immune checkpoint, and T-effector cell- and IFN-γ-related cytotoxic gene expression in the high-risk group than in the low-risk group. Conclusion: The 12-gene prognostic risk model can reliably predict overall survival outcomes and is strongly associated with the tumor immune microenvironment of ccRCC.

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle loss, affecting 30–60% of patients with advanced renal cell carcinoma (RCC). It significantly impacts treatment tolerance, quality of life, and prognosis, yet its diagnosis and management remain challenging due to fragmented RCC-specific evidence, particularly in the era of immune checkpoint inhibitor (ICI)-based therapy. The pathogenesis involves persistent systemic inflammation, metabolic reprogramming, and tumor–host interactions. The IL-6/STAT3 and TNF-α/NF-κB pathways are central to muscle catabolism, while tumor-derived mediators such as GDF15 and PTHrP, along with mitochondrial dysfunction, further drive cachexia progression. For prognostic assessment, CT-derived skeletal muscle mass evaluation combined with systemic inflammatory and nutritional biomarkers—including neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), and cachexia index (CXI)—has improved risk stratification in advanced RCC. Preclinical and emerging clinical data suggest that targeted therapies may partially attenuate cachexia by modulating inflammatory signaling, while multimodal interventions integrating nutritional support and exercise rehabilitation remain the cornerstone of management. Novel strategies, such as inhibition of the GDF15/GFRAL axis, are under active investigation. Future research should prioritize identification of early biomarkers, standardization of cachexia assessment, and prospective evaluation of cachexia-directed interventions in the immunotherapy era. Integrating cachexia assessment into routine practice may ultimately enable personalized treatment and improve long-term outcomes for patients with advanced RCC.

Background/Objectives: This study evaluated neoadjuvant disitamab vedotin plus programmed cell death protein 1 (PD-1) blockade and associations of post-treatment neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with response and progression-free survival (PFS) in muscle-invasive bladder cancer. Methods: This single-center retrospective cohort included 71 patients with cT2–T3N0M0, human epidermal growth factor receptor 2 (HER2)-expressing disease treated between September 2021 and October 2025. Logistic regression and receiver operating characteristic analyses evaluated response endpoints; Kaplan–Meier and Cox methods evaluated PFS. Benjamini–Hochberg correction was applied separately to response analyses. Results: Complete response (CR), objective response, and disease control rates were 66.2%, 84.5%, and 88.7%. Of 47 CRs, 5 were cystectomy-confirmed pathological CR (pCR) and 42 were clinical CR (cCR). Response associations did not remain significant after correction (minimum q = 0.082). AUCs were 0.659–0.708. In a two-variable Cox model based on 14 PFS events, treatment cycles (HR 0.615, 95% CI 0.419–0.903; p = 0.013) and SII per 100 units (HR 1.205, 95% CI 1.073–1.355; p = 0.002) were associated with PFS, but these estimates require cautious interpretation. Two deaths occurred. Conclusions: Neoadjuvant disitamab vedotin plus PD-1 blockade showed promising antitumor activity. The pooled CR endpoint may overestimate pathological response and is not directly comparable with cystectomy-confirmed pCR. Without standardized pretreatment NLR and SII measurements, reverse causality cannot be excluded. Response associations and PFS findings based on 14 events require cautious interpretation and prospective validation.

Background/Objectives: The purpose of this study was to investigate the association between HER-2 expression and clinicopathological characteristics, biochemical recurrence (BCR) rate, and BCR-free survival in localized prostate cancer (PCa) patients after radical prostatectomy (RP). Methods: Between January 2018 and December 2019, 44 patients with pathologically confirmed localized PCa who underwent RP were included in this study. According to the expressed level of HER-2 protein, patients were divided into four cohorts: cohort-1 (HER-2 0), cohort-2 (HER-2 1+ or 2+), cohort-3 (HER-2 0 or 1+), and cohort-4 (HER-2 2+); the clinicopathological and clinical outcomes were analyzed and compared between cohort-1 and cohort-2, and cohort-3 and cohort-4, respectively. Univariable and multivariable COX regression models and Kaplan–Meier curves were used to determine the association between HER-2 expression and clinicopathological outcomes, including Gleason score (GS), pathological T (pT) stage, positive surgical margins (PSM), and BCR-free survival, respectively. Results: The median follow-up time was 43 months (IQR 35–49). Among the 44 patients, 20 (45.5%) exhibited HER-2 immuno-reactivity, including 14 (31.8%) with HER-2 1+, 6 (13.64%) with HER-2 2+, and 0 (0%) with HER-2 3+ staining. The proportion of patients with PSM was significantly lower in the HER-2 0 group than in those with HER-2 1+ or 2+ (25.0% vs. 65.0%, p = 0.008). Multivariable logistics regression models revealed that HER-2 1+ or 2+ was an independent risk factor that was strongly associated with a higher proportion of PSM (OR, 2.69; 95% CI, 0.62–11.71, p = 0.042). A total of 18 (40.9%) patients experienced BCR after surgery, including 6 (25%) in cohort-1 and 12 (60.0%) in cohort-2 (p = 0.019), as well as 13 (34.2%) in cohort-3 and 5 (83.3%) in cohort-4 (p = 0.023). Kaplan–Meier analysis showed that patients in cohort-1 (HER-2 0) had significantly longer BCR-free survival than those in cohort-2 (HER-2 1+ or 2+) (p < 0.001), and those in cohort-3 had longer BCR-free survival than those in cohort-4 (p < 0.001). Furthermore, patients with PSM showed significantly shorter BCR-free survival compared to those with patients with negative surgical margins (NSM) (p = 0.005). Multivariable Cox regression analysis revealed that HER-2 1+, 2+ (HR, 17.00; 95% CI, 1.38–210.22, p < 0.001), HER-2 2+ (HR, 2.85; 95% CI, 1.23–3.25, p = 0.004), and PSM (HR, 6.12; 95% CI, 3.08–11.72, p = 0.007) were all significant independent predictors of BCR following surgery. Conclusions: HER-2 expression is a common phenomenon in PCa; nearly half of the proportion of localized PCa had HER-2 1+ or 2+, but the cases that expressed HER-2 3+ were rare. Cases with HER-2 1+ or 2+ were more likely to develop BCR compared with HER-2 0. The HER-2 1+ or 2+ expression was closely associated with a higher incidence of PSM and was an independent predictor of shorter BCR-free survival in patients with localized prostate cancer after radical prostatectomy.

Bladder cancer is one of the most common malignancies of the urinary system. Identifying new potential therapeutic targets and exploring molecular mechanisms are crucial for improving treatment and prognosis. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 2, known to play a key role in various physiological and pathological processes, has an unclear function and mechanism of action in bladder cancer. We employed bioinformatics analysis and immunohistochemistry to assess the role of HCN2 in bladder cancer, integrating in vitro and in vivo models to evaluate the impact of HCN2 on cell behavior. Molecular interactions were characterized using immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. Our investigation revealed a significant upregulation of HCN2 in bladder cancer tissues, which was predictive of a poorer clinical outcome. Functionally, HCN2 knockdown in bladder cancer impeded cell proliferation, induced apoptosis, and curtailed migration and invasion. Mechanistically, the overexpression of HCN2 contributed to the translocation of the REST transcription factor into the nucleus and facilitated its binding to the BGN promoter for transcriptional activation of its expression. This regulatory mechanism was shown to suppress ferroptosis, a form of regulated cell death, thereby enhancing the proliferative and tumorigenesis of bladder cancer cells. This study uncovers the novel mechanism by which HCN2 regulates ferroptosis via the REST-BGN axis, affecting bladder cancer cell behavior, and provides new perspectives and strategies for future clinical treatment.