DDC expression correlates with NEPC signatures in mouse models and human datasets.

Serotonin-associated genes and pathways are enriched in NEPC.

Benign prostatic hyperplasia (BPH) is a common urological disease in middle-aged and elderly men. Its incidence increases continuously with age, which significantly affects patients' quality of life and may even be life-threatening. As population aging intensifies, BPH has become an increasingly prominent public health problem. Existing studies suggest that the occurrence and progression of BPH are associated with multiple factors. However, there is currently a lack of systematic and standardized guidance on managing risk factors for BPH in clinical practice. Focusing on existing evidence and integrating clinical experts' opinions, this consensus formulates 20 items recommendations aiming to promote the standardized management of risk factors influencing the occurrence and progression of BPH, in order to delay its age of onset, slow clinical progression, and reduce the disease burden.

Upper tract urothelial carcinoma (UTUC) poses diagnostic challenges due to its anatomical complexity and limited accessibility. This prospective multicenter study (NCT05043662) evaluated the diagnostic performance of UroCAD, a novel non-invasive assay based on chromosomal copy number variation (CNV) analysis, in 244 patients with suspected UTUC or benign upper urinary tract conditions. Urine samples were analyzed for arm-level chromosomal aberrations (|Z-score|≥ 3.21), with histopathology as the reference standard. UroCAD demonstrated excellent diagnostic accuracy: sensitivity 91.0

Serotonylation-dependent redistribution of H3K4me3 distinguishes neuroendocrine and luminal transcriptional programs.

Background Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare subtype of kidney malignancy with poor prognosis. Standard of care for advanced FH-RCC has not been established, although our prior retrospective study showed encouraging antitumor activity of immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combinations. Objective We aimed to conduct an investigator-initiated prospective study to assess the efficacy and safety of tislelizumab plus lenvatinib as a first-line treatment for patients with advanced FH-RCC. Methods In this single-arm, open-label, phase 2 trial, adult patients with previously untreated, pathologically confirmed, unresectable advanced or metastatic FH-RCC, and at least one measurable lesion per RECIST 1.1 were eligible for enrollment. All enrolled patients received tislelizumab 200 mg intravenously every three weeks plus lenvatinib 20 mg orally once daily until disease progression, intolerable toxicity, or withdrawal of consent. This trial is registered with ClinicalTrials.gov (NCT05877820) and closed enrollment. The primary end point was objective response rate (ORR) as assessed by RECSIT 1.1. Secondary endpoints included progress-free survival, overall survival, disease control rate, duration of response, clinical benefit rate and treatment-related adverse events (TRAEs) assessment. Efficacy and safety were analyzed in all treated patients. Correlation between circulating metabolic biomarker dynamics and clinical response was investigated as an exploratory endpoint. Results From September 5, 2023, to December 10, 2024, 25 patients were screened and 20 were eligible to receive treatment. Median age was 41.5 years (IQR: 30–50) and 80% of patients were male. ECOG performance status was 1 or 2 in 40% of patients. Patients were classified as favorable, intermediate, or poor risk group in three (15%), eleven (55%), and six (30%) patients respectively per IMDC categorization. FH germline mutation was identified in 15/20 (75%) patients; the remainder were considered to carry biallelic somatic FH alterations. As data cutoff, the median follow-up was 17.8 months (IQR: 12.2–23.0). Nineteen patients achieved a confirmed objective response (ORR: 95%; 95% CI: 75.1–99.9), including four (20%) with a complete response and 15 (75%) with a partial response as the best response, with a median duration of response of 19.2 months (95%CI: 16.3-NR). The median PFS was 20.7 months (95%CI: 17.8-NR). Two-year overall survival rate was estimated as 89.7% (95% CI: 77.2–100). Grade ≥ 3 TRAEs occurred in 9/20 (45%) patients; and dose interruption, reduction or discontinuation of any study agent occurred in 14/20 (70%) patients. We found that circulating succinyl-adenosine and succinic-cysteine tracked radiographic tumor burden assessed by RECIST 1.1 in 16/20 (80%) patients. The main limitation is the single-centre and single-arm design, and the sample size is limited. Conclusions Tislelizumab plus lenvatinib has favorable antitumor activity in patients with previously untreated advanced FH-RCC, with a safety profile consistent to that of previous reports, which shows potential as a first-line treatment option. Circulating succinate-modifying metabolites may act as potential biomarkers for real-time treatment response monitoring and for the detection of early treatment failure.

Serotonylation-dependent chromatin remodeling coordinates SOX9, EZH2, and ASCL1 regulatory networks in NEPC.

Chromatin and transcriptomic effects of histone serotonylation in NEPC models.

Prostate cancer (PCa) remains a major global health burden, yet current screening tools often lead to overdiagnosis due to low specificity, highlighting the urgent need for more precise diagnostic approaches. Prostatic fluid (PSF) represents a promising but underexplored biofluid with exceptional diagnostic potential due to its direct contact with the PCa microenvironment. Here, we employed molecule-level interpretable surface-enhanced Raman spectroscopy (SERS) to comprehensively investigate PCa-associated alterations in two PSF components including metabolites and small extracellular vesicles (sEVs) and explored their potential interrelations via correlation analysis. Through molecule-resolvable SERS spectral set (MORE SERSome) technique, we identified ergothioneine and deoxyguanosine as differential metabolites between PCa and benign prostatic hyperplasia patients. We further constructed a fusion diagnostic model by integrating metabolites and sEVs information. The fusion model significantly outperformed the diagnostic accuracy by applying any single component, suggesting diagnostic complementarity between PSF metabolites and sEVs. Integration with clinical variables such as age and plasma prostate-specific antigen concentration further enhanced performance with the area under the curve as high as 0.93 for PCa diagnosis, substantially surpassing existing screening methods. These findings strengthen the importance of in-depth analysis of specific PSF components and further promise the potential of SERS-based PSF profiling as a noninvasive strategy for PCa diagnosis and biopsy guidance.

Transcriptomic stratification of prostate cancer patient cohorts reveals serotonin-axis activation in NE⁺ tumors.

SOX2 directly regulates DDC transcription and co-evolves with DDC during NEPC progression.

Pharmacologic inhibition of the serotonin axis suppresses neuroendocrine features in vitro and in vivo.

Supplementary Table. List of antibodies and small molecules used in this project

3112 Background: ADT plus NHA have been approved for PC of different stages. However, patients (pts) inevitably develop drug resistance, and AR mutations are a common cause of this resistance. HRS-5041 is a novel, oral, highly effective AR degrader that specifically targets the AR wild type (AR WT) and clinically relevant AR LBD mutants. We conducted a phase 1 trial to assess HRS-5041 in NHA-resistant mCRPC. Methods: Pts with mCRPC who had progressed on ≥1 NHA and ≥1 taxane chemo (unless refused or not indicated to chemo) were eligible. Pts orally received HRS-5041 at 30–540 mg QD or 240–300 mg BID during dose-escalation (DE), followed by dose or indication expansion at 180–360 mg QD or 240-300 mg BID. 240 mg BID and 360 mg QD were selected for dose optimization. The primary endpoints were DLT, MTD, and RP2D. Results: As of Dec. 12, 2025, 156 pts were enrolled, including 77 with AR-LBD mutation and 79 with AR-LBD WT. During DE, no DLT occurred. MTD was not reached. TRAEs were reported in 133 (85.3%) pts; the most common were anemia (38.5%), decreased appetite (25.6%), and diarrhea (24.4%). Grade ≥3 TRAEs and serious TRAEs occurred in 20 (12.8%) and 4 (2.6%) pts. No TRAEs led to death. Among all evaluable pts, rate of PSA reduction ≥50% was 0 for 1 pt at 30 mg QD, 0 for 4 pts at 90 mg QD, 17.4% for 23 pts at 180 mg QD, 32.1% for 53 pts at 360 mg QD, 40.0% for 5 pts at 540 mg QD, 35.7% for 56 pts at 240 mg BID, and 11.1% for 9 pts at 300 mg BID. Data by AR-LBD status for expanded doses are shown in table. Both 360mg QD and 240mg BID groups showed excellent PSA response rates and rPFSs, regardless of AR-LBD status. Among pts with AR-LBD mutations, the 240 mg BID group showed a superior rate of PSA reduction ≥50% and a higher 8-month rPFS rate than the 360 mg QD group. Notably, 2 patients in the 240 mg BID group achieved CR, including 1 with liver metastases. Conclusions: HRS-5041 showed tolerable safety and promising antitumor activity in pretreated mCRPC. A phase 3 study is currently underway in mCRPC pts with AR-LBD mutation, with a recommended dose of 240mg BID. Clinical trial information: NCT05942001 . Efficacy outcomes. Dose 180 mg QD 180 mg QD 360 mg QD 360 mg QD 240 mg BID 240 mg BID AR-LBD status AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT PSA reduction ≥30% * 5 (50.0) 1 (7.7) 15 (48.4) 8 (36.4) 17 (54.8) 7 (28.0) PSA reduction ≥50% * 3 (30.0) 1 (7.7) 10 (32.3) 7 (31.8) 15 (48.4) 5 (20.0) rPFS, mo † NR (2.2–NR) 5.8 (2.1–8.6) 11.0 (5.5–NR) 13.8 (8.2–NR) 11.0 (8.2–NR) NR (3.5–NR) 8-month rPFS rate † 53.3 (17.7–79.6) 32.6 (5.8–64.3) 58.1 (35.6–75.2) 82.9 (55.7–94.2) 85.3 (60.2–95.1) 71.2 (46.4–86.0) ORR # 2 (66.7) 0 0 0 3 (42.9) 1 (11.1) Data are n (%) or median (95% CI). * Assessed in pts who had at least one post-baseline PSA assessment or who discontinued treatment due to death/clinical progression without post-baseline PSA assessment; N was 10, 13, 31, 22, 31, and 25. † Assessed in full analysis set; N was 10, 14, 32, 23, 33, and 25. # Assessed in pts with baseline target lesions; N was 3, 4, 10, 5, 7, and 9.

Supplementary Table S3. 5-HT pathway drugs in high-throughput drug screening

Personalized vaccines demonstrate remarkable potential in leveraging tumor-specific adaptive immunity for cancer therapy. Nevertheless, current platforms face persistent challenges, including premature systemic clearance and imprecise antigen-presenting cell targeting, culminating in transient and inefficient antitumor immunity. Furthermore, the technical complexity, extended timelines, and prohibitive costs required for tumor-specific neoantigen identification continue to impede the clinical translation of personalized cancer vaccines. Here, we report a tumor-derived extracellular vesicle-based scaffold vaccine that elicits robust and durable antitumor immunity for personalized cancer immunotherapy. Following subcutaneous administration, the in situ-formed hydrogel vaccine serves as a sustained reservoir for tumor-derived extracellular vesicle antigens and adjuvants while recruiting antigen-presenting dendritic cells to accumulate within the scaffold. Upon exposure to this antigen-rich depot, immature dendritic cells undergo efficient activation, with subsequently matured dendritic cells migrating to draining lymph nodes, where they induce potent and persistent tumor-specific CD8(+) T-cell responses that suppress tumor progression across multiple murine models. Specifically, when using tumor-derived extracellular vesicles isolated from surgically excised tumor tissues, the patient-tailored vaccines demonstrate remarkable efficacy in preventing postoperative recurrence. Our findings validate the robust and durable therapeutic efficacy of this vaccine platform, highlighting its potential as a customizable strategy for personalized cancer immunotherapy.

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive kidney cancer with no established standard of care. This phase 2 trial (NCT05877820) assessed first-line tislelizumab plus lenvatinib in advanced FH-RCC (N = 20). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. After a median follow-up of 20.2 months, ORR was 95% (95% CI 75.1–99.9), and DCR was 100% (95% CI 83.2–100). Median PFS was 20.7 months (95% CI 17.8–NR), median DOR was 19.2 months (95% CI 16.3–NR) and 2-year OS rate was 89.7% (95% CI 77.2–100). Grade ≥3 treatment-related adverse events occurred in 45% of patients. Circulating succinyl-adenosine and succinic-cysteine tracked radiographic tumor burden in 80% of patients. Limitations include the single-center, single-arm design, and limited sample size. These results support tislelizumab plus lenvatinib as a potential first-line option for advanced FH-RCC, with favorable antitumor activity and manageable safety profile. Circulating succinate-modifying metabolites may complement response monitoring but require further validation. Effective first-line treatments for fumarate hydratase-deficient renal cell carcinoma remain poorly defined, despite promising activity of immune checkpoint inhibitor– based combinations. There these authors report efficacy outcomes of a phase 2 clinical trial on tislelizumab plus lenvatinib in fumarate hydratase-deficient renal cell carcinoma patients.

As one of the predominant male malignancies globally, prostate cancer (PCa) transitions to a treatment-refractory phase upon metastasis, for which no curative modalities currently exist. Tumor-associated macrophages (TAMs), a crucial component of the tumor microenvironment (TME), primarily adopt a metastasis-promoting M2 phenotype. However, the mechanisms underlying the TAM-cancer cell crosstalk and resultant PCa metastasis remain elusive. In this study, primary lesions of metastatic PCa (mPCa) exhibit both greater infiltration of M2 macrophages and a higher proportion of M2 macrophage-derived extracellular vesicles (M2 EVs) compared to those of non-metastatic PCa (nmPCa). Furthermore, M2 EVs can be internalized by PCa cells, promoting a mesenchymal-like state (MLS) in PCa and affecting tumor metastasis. Mechanistically, thioredoxin domain-containing 5 (TXNDC5) mRNA encapsulated in M2 EVs contributes to MLS of DU145 and PC3 cells, enhancing migration and invasion. Single-vesicle particle analysis confirms that TXNDC5 mRNA encapsulated within M2 EVs can be horizontally transferred to target cells, where it is translated to produce functional proteins. In conclusion, our study demonstrates that M2 macrophages can promote MLS and metastasis of PCa through EV-mediated horizontal mRNA transfer. A novel role of EVs in the communication between the TME and tumor cells is discovered, offering new insights into tumor metastasis.

Transcriptomic and functional effects of DDC and SLC6A4 overexpression in prostate cancer cells.