bims-meproc 2026-04-12 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–04–12
twenty-two papers selected by
Grigor Varuzhanyan, UCLA

EGFR- and HER3-targeted bispecific antibody-drug conjugate demonstrates anti-tumor activity in metastatic castration-resistant prostate cancer.
Targeting the RNA-binding motif protein 15 suppresses prostate cancer progression and hormone therapy resistance by promoting androgen receptor degradation.
Guben Qingyuan Herbal Medicine Delays Enzalutamide Resistance in Prostate Cancer by Alleviating Tumor Hypoxia and Reprogramming Energy Metabolism in Cancer Stem Cells.
Indole-3-propionic acid suppresses prostate cancer by inducing cell cycle arrest and apoptosis associated with p53 activation.
Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
Identification of biomarkers for non-invasive diagnosis and risk stratification in prostate cancer using NMR-based metabolomics and machine learning.
Folate Receptor α Contributes to Radiation Resistance in Neuroendocrine Prostate Cancer by Regulating Redox Homeostasis.
New insights into prostate cancer progression: a focus on vitamin D signaling.
Regulatory B cells and SIVA1-LAG3 immune suppression predict poor prognosis in prostate cancer.
NSUN2/ALYREF-mediated RNA m5c modification promotes anoikis resistance of prostate cancer through activating autophagy.
PCSK9 promotes prostate cancer via facilitating intratumoral cholesterol accumulation and enhancing immunosuppressive tumor microenvironment.
Therapy-induced androgen receptor signaling as a candidate upstream driver of B7-H3-linked immune exclusion in melanoma: mechanisms and translational opportunities.
The Impact of Tumor Microenvironmental Acidity on Bicalutamide Sensitivity in Prostate Cancer Cells.
Androgen Receptor-Induced Lactoferrin Accelerates Prostate Tumorigenesis Through Modulating Ferroptosis.
Mapping the immune landscape of PCa: From tumor microenvironment to therapeutics.
Epigenetic dysregulation and biological function of PDX1 in prostate cancer.
Mechanism and therapeutic significance of ARV-110 combined with a PDGFR inhibitor for the induction of apoptosis in castration-resistant prostate cancer cells through the ROS/JNK pathway.
Protocol for generating and characterizing Matrigel-free prostate cancer patient-derived organoids.
Astragaloside IV directly targets PPP1R14B to sensitize prostate cancer to anti-PD-1 immunotherapy by remodeling the CX3CL1/CD8+ T cell axis.
Androgen receptor pathway inhibitor intensification in non-metastatic hormone-sensitive prostate cancer: current evidence and clinical implications.
A Shot in the Dark: Unprecedented Complete Radiologic Response of Metastatic Prostate Cancer to Single-Dose Androgen Deprivation Therapy (ADT).
Urologic Bacteriome: The Hero or the Villain in Prostate Cancer Onset, Progression, and Treatment?

J Clin Invest. 2026 Apr 07. pii: e201090. [Epub ahead of print]

EGFR- and HER3-targeted bispecific antibody-drug conjugate demonstrates anti-tumor activity in metastatic castration-resistant prostate cancer.

Bangwei Fang, Xiaomeng Li, Ying Lu, Weiwei Ma, Hualei Gan, Tingwei Zhang, Qi Liu, Beihe Wang, Zixian Wang, Yi Zhu, Hai Zhu, Sa Xiao, Xiaojie Bian, Gonghong Wei, Dingwei Ye, Yao Zhu.

  Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody-drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative mCRPC patient with high EGFR/HER3 expression who achieved a rapid and durable clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and nominate ABCG2 as a rational target for overcoming resistance.

Keywords:  Clinical Research; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI201090
Mol Biomed. 2026 Apr 08. pii: 47. [Epub ahead of print]7(1):

Targeting the RNA-binding motif protein 15 suppresses prostate cancer progression and hormone therapy resistance by promoting androgen receptor degradation.

Bintao Hu, Le Li, Zhenghui Jin, Qinyu Li, Yue Wu, Jie Chen, Jihong Liu, Chenglin Han, Tao Wang.

  Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Keywords:  AR; DDB1; M6A; Prostate cancer; RBM15; YTHDF2

DOI:  https://doi.org/10.1186/s43556-026-00428-1
J Ethnopharmacol. 2026 Apr 08. pii: S0378-8741(26)00518-0. [Epub ahead of print] 121667

Guben Qingyuan Herbal Medicine Delays Enzalutamide Resistance in Prostate Cancer by Alleviating Tumor Hypoxia and Reprogramming Energy Metabolism in Cancer Stem Cells.

Xudong Zhu, Xixi Ji, Haoran Chen, Suping Fang, Jiazheng Wang, Hao Liu.

   ETHNOPHARMACOLOGICAL RELEVANCE: Enzalutamide resistance is a major clinical bottleneck limiting the therapeutic efficacy of castration-resistant prostate cancer (CRPC). Enzalutamide treatment can exacerbate tumor hypoxia, which is a critical contributor to the development of its resistance. The traditional Chinese formula Guben Qingyuan Herbal Medicine (GBQY), coupled with enzalutamide, has demonstrated potential in delaying enzalutamide resistance. Nevertheless, its interaction with the tumor microenvironment (TME) remains insufficiently investigated.
AIM OF THE STUDY: This study aims to explore the anti-tumor role and mechanism of GBQY on CRPC.
MATERIALS AND METHODS: Enzalutamide-resistant prostate cancer (PC) cell models and corresponding xenograft models were established to evaluate the therapeutic efficacy of GBQY combined with enzalutamide. A hypoxia-sensitive PC xenograft model was constructed to identify hypoxic tumor cell populations in vivo. The correlation between ATP-citrate lyase (ACLY) and hypoxia-inducible factor (HIF)-1α was predicted via bioinformatics analysis and subsequently validated by chromatin immunoprecipitation (ChIP) assay. The impact of hypoxia and ACLY inhibition/knockdown on PC stem cells (PCSCs) was examined using metabolomics. Additionally, a PCSC xenograft model was used to verify the signaling pathways underlying the therapeutic action of GBQY in combination with enzalutamide.
RESULTS: The combinational therapy of GBQY and enzalutamide significantly delayed the occurrence of enzalutamide resistance. This effect was mediated by alleviating tumor hypoxia, accompanied by attenuated expression of cancer stem cell (CSC) markers CD44 and CD133 in tumor tissues. Xenograft-isolated hypoxia tumor cells consisted of a larger proportion of cells exhibiting CSC-like characteristics. Under hypoxic conditions, elevated HIF-1α levels likely functioned as a transcription factor, upregulating ACLY expression. Subsequent ACLY activation induced a specific energy metabolic reprogramming (EMR), characterized by enhanced glucose uptake and pyruvate production. EMR shifted the glycolytic flux towards mitochondrial pyruvate and citrate, thereby accumulating cytosolic acetyl-CoA via ACLY activity. This metabolic phenotype facilitated β-catenin acetylation, triggering the Wnt/β-catenin signaling cascade crucial to enzalutamide resistance in PC.
CONCLUSION: These findings provide preclinical evidence supporting the combined application of GBQY and enzalutamide in CRPC treatment. By elucidating the interaction between Traditional Chinese Medicine (TCM) and conventional anti-tumor therapy within TME, this study offers mechanistic insights into resistance modulation and paves the way to optimizing the precision of TCM-based therapeutic strategies in PC management.

Keywords:  ATP-citrate lyase; Castration-Resistant Prostate Cancer; Guben Qingyuan Herbal Medicine; Hypoxic Tumor Microenvironment; Traditional Chinese Medicine

DOI:  https://doi.org/10.1016/j.jep.2026.121667
Front Oncol. 2026 ;16 1759301

Indole-3-propionic acid suppresses prostate cancer by inducing cell cycle arrest and apoptosis associated with p53 activation.

Yongneng Huang, Xinwei Liu, Yifan Wu, Shilin Li, Yang Shen, Hongyuan Wan, Yuwei Zhang, Ninghan Feng.

   Introduction: Prostate cancer (PCa) poses a significant health burden worldwide, with castration-resistant progression representing a major therapeutic challenge. While gut microbiota metabolites have been increasingly linked to tumor development, the specific role of indole-3-propionic acid (IPA) in PCa remains unclear. This study explores the direct antitumor effects and molecular mechanisms of IPA in PCa progression.
Methods: Using untargeted metabolomics, circulating metabolite profiles were characterized in serum samples from PCa patients and benign prostatic hyperplasia controls. The antitumor effects of IPA on PCa cells were evaluated with in vitro assays, including colony formation, wound healing, transwell migration, and flow cytometry for cell cycle and apoptosis analysis. In vivo efficacy of IPA was tested using a xenograft mouse model. Transcriptome sequencing (RNA-seq) and gene set enrichment analysis identified key biological processes. Western blot and quantitative PCR validated activation of the p53 signaling pathway.
Results: Metabolomic analysis revealed markedly lower IPA levels in PCa patients, particularly in high-grade PCa. In vitro assays showed that IPA treatment effectively reduced PCa cell proliferation, migration, and invasion. In vivo studies with xenograft models demonstrated that IPA significantly slowed tumor growth. RNA-seq and gene set enrichment analysis pointed to cell cycle regulation as the main biological process affected by IPA. Flow cytometry confirmed that IPA caused cell cycle arrest and increased apoptosis in PCa cells. Mechanistic studies indicated that IPA specifically activates the p53-p21-RB signaling axis. Western blot and qPCR confirmed the increased expression of p53 and p21 after IPA treatment.
Conclusion: IPA inhibits PCa cell proliferation, migration, and invasion, while inducing cell cycle arrest and apoptosis concurrent with the activation of the p53 signaling pathway, suggesting its potential as a new therapeutic option for PCa. These findings position IPA not only as a potential prognostic biomarker but also as a promising candidate for microbiota-based metabolic intervention in PCa management.

Keywords:  cell apoptosis; cell cycle; indole-3-propionic acid; p53-p21-RB; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2026.1759301
Mol Cancer Ther. 2026 Apr 09.

Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao.

Resistance to PARP inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from TCGA and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and re-sensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts oxidative phosphorylation and induces ferroptosis, providing a strong rationale for combination strategies with PARP inhibitors to overcome drug resistance.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1157
NPJ Precis Oncol. 2026 Apr 08.

Identification of biomarkers for non-invasive diagnosis and risk stratification in prostate cancer using NMR-based metabolomics and machine learning.

Xi Zhang, Minjiang Chen, Binbin Xia, Binrui Liu, Xiaoya Lin, Hanyang Tao, He Wang, Tengfei Gu, Jie Li, Baijun Dong, Hongchang Gao.

The non-invasive diagnosis and risk stratification of prostate cancer (PCa) remain clinically challenging due to the limited specificity of prostate-specific antigen (PSA). In this retrospective study, we applied a comparative machine learning (ML) framework to rank and select biomarkers from serum 1H nuclear magnetic resonance (NMR)-based metabolomics, subsequently developing three sequential metabolite panels. These metabolite-based models effectively distinguished overall PCa from benign prostatic hyperplasia (BPH), clinically non-significant prostate cancer (cnsPCa) from BPH, and clinically significant prostate cancer (csPCa) from cnsPCa. All models achieved areas under the curve (AUC) consistently above 0.9 in both discovery and validation cohorts, without incorporating clinical variables such as age or PSA. Decision curve analysis (DCA) further confirmed their superior clinical utility over the current PSA-based strategy. This study underscores the potential of ML-driven metabolomics for accurate, non-invasive diagnosis and effective risk stratification of PCa, which could significantly improve patient management and reduce unnecessary interventions.

DOI: https://doi.org/10.1038/s41698-026-01406-0
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714502. [Epub ahead of print]

Folate Receptor α Contributes to Radiation Resistance in Neuroendocrine Prostate Cancer by Regulating Redox Homeostasis.

Hira Lal Goel, Tao Wang, Boris S Dimitrov, Ayush Kumar, Christi A Silva, Thomas J FitzGerald, Arthur M Mercurio.

Ionizing radiation can be an effective therapy for prostate cancer. Unfortunately, however, more aggressive prostate cancers such as neuroendocrine prostate cancer (NEPC) are often radiation resistant, which contributes to their high degree of morbidity and mortality. In this study, we used an unbiased approach to identify novel mechanisms that contribute to resistance to radiation and that are associated with neuroendocrine differentiation. Specifically, we compared the expression of cell surface proteins by mass spectrometry in prostate cancer cell lines that had been either untreated or treated with radiation to induce resistance, a process that also promotes neuroendocrine differentiation. Among the proteins identified by this screen, we focused on folate receptor α (FRα) because of its known biological functions and the fact that it is a validated therapeutic target. Our data reveal that FRα has a causal role in enabling prostate cancer cells to resist radiation. Importantly, we also demonstrate that the expression of FRα is regulated by HIF-1α, which also has a causal role in radiation resistance and neuroendocrine differentiation. Given that the ability of cells to resist damage and death in response to ionizing radiation depends largely on their ability to buffer the substantial increase in reactive oxygen species (ROS) that is generated by radiation, we also demonstrate that the folate-FRα axis promotes radiation resistance by sustaining intracellular glutathione levels that buffer this increase in ROS. In summary, the data reported here highlight a novel role for FRα in resistance to ionizing radiation that is intimately associated with the hypoxic microenvironment of NEPC and the ability of the folate-FRa axis to maintain redox homeostasis.

DOI: https://doi.org/10.64898/2026.03.26.714502
J Steroid Biochem Mol Biol. 2026 Apr 08. pii: S0960-0760(26)00085-3. [Epub ahead of print] 107019

New insights into prostate cancer progression: a focus on vitamin D signaling.

Vanessa Friedrich, Gilles Laverny.

  Prostate cancer (PCa) is one of the most frequent cancer in men of western society. Whereas the therapeutic options for localized PCa are efficient, those for advanced forms lead to resistance and are of a poor outcome. Thus, it is of utmost importance to understand the mechanisms underlying PCa progression to identify biomarkers predicting tumor evolution and novel therapeutic options. This review summarizes the current knowledge on PCa progression, treatments and preclinical approaches, with a specific emphasis on the role of vitamin D signaling.

Keywords:  , vitamin D; castration resistance; chemoresistance; genetically engineered mouse models; patient derived organoids; prostate cancer; vitamin D receptor

DOI:  https://doi.org/10.1016/j.jsbmb.2026.107019
Biomol Biomed. 2026 Apr 10.

Regulatory B cells and SIVA1-LAG3 immune suppression predict poor prognosis in prostate cancer.

Weicheng Tian, Yize Li, Jinchuang Li, Chenyu Liang, Shanghua Cai, Biyan Wen, Zeheng Tan, Zhenjie Wu, Yulin Deng, Zige Liu, Yongding Wu, Haiyin Xiao, Weide Zhong, Huichan He, Chitin Hon, Jianheng Ye.

Prostate cancer (PCa) is among the most prevalent malignancies affecting men globally. The immunosuppressive characteristics of the tumor microenvironment significantly hinder the effectiveness of immunotherapeutic strategies. B cells have a dual role in immune responses, with regulatory B cells (Bregs) promoting immune tolerance through the secretion of immunosuppressive cytokines, facilitating tumor immune evasion. However, the specific role of Bregs in prostate cancer remains inadequately understood. In this study, we systematically identified Breg subpopulations in prostate cancer using single-cell RNA sequencing (scRNA-seq), multi-omics analysis, and machine learning techniques, while also investigating their association with clinical prognosis. Our analysis revealed that increased infiltration of Bregs is strongly correlated with shorter biochemical recurrence-free survival (BCRFS). Additionally, higher expression levels of SIVA1 apoptosis-inducing factor (SIVA1) were positively associated with the immune checkpoint lymphocyte-activation gene 3 (LAG3). Utilizing Breg-related prognostic genes (BRPGs), we developed a novel model for predicting BCRFS, which we validated across multiple independent cohorts. Further immunohistochemical analysis confirmed the positive correlation between elevated SIVA1 expression and poor prognosis, as well as its association with LAG3. Collectively, these findings provide new insights into the immune microenvironment of prostate cancer and suggest that Breg-related characteristics and the SIVA1-LAG3 relationship in tumor cells may represent promising therapeutic targets for future research.

DOI: https://doi.org/10.17305/bb.2026.14056
Oncogene. 2026 Apr 07.

NSUN2/ALYREF-mediated RNA m5c modification promotes anoikis resistance of prostate cancer through activating autophagy.

Guangyu Sun, Shuaiqi Chen, Mingzhe Chen, Xiong Xiao, Ruoxuan Zhang, Hao Ye, Yuxuan Guo, Ranlu Liu.

Prostate cancer is the most common malignant tumor among men worldwide, severely threatening the health of aging males. RNA 5-methylcytosine (m5C) modification has been demonstrated to play a significant role in the initiation and progression of various tumors. However, the role of ALYREF, a key methyl-recognizing protein for m5c modification, is still unclear in prostate cancer. In our study, we found that knockdown of ALYREF reduces the proliferation, invasion and metastasis of prostate cancer. ALYREF promotes anoikis resistance in prostate cancer by positively regulating BPIP3 and thereby activating autophagy. Mechanistically, we found that ALYREF is a methylation recognition protein that directly and specifically recognizes the m5c site of BNIP3 mRNA and enhances the stability of BNIP3 mRNA, which activates autophagy in prostate cancer cells, and thus enhances the anoikis resistance and metastatic ability of cancer cells. Overall, our study revealed the important role of ALYREF-mediated m5C methylation modification in the mechanisms of autophagy and anoikis resistance in prostate cancer, providing an important molecular target for the treatment of advanced prostate cancer.

DOI: https://doi.org/10.1038/s41388-026-03762-4
J Adv Res. 2026 Apr 06. pii: S2090-1232(26)00299-7. [Epub ahead of print]

PCSK9 promotes prostate cancer via facilitating intratumoral cholesterol accumulation and enhancing immunosuppressive tumor microenvironment.

Yan Gu, Fengxiang Wei, Ying Dong, Xiaozeng Lin, Yingying Su, Geoffrey Wood, Nabil G Seidah, Michael Bonert, Geoff Werstuck, Tariq Aziz, Pierre Major, Damu Tang.

   INTRODUCTION: Cholesterol plays critical roles in prostate cancer (PCa) proliferation, immune evasion, and androgen signaling. PCSK9 regulates cholesterol metabolism. Its role in PCa remains unclear.
OBJECTIVE: To investigate PCSK9's function in promoting PCa progression and the underlying mechanisms.
METHODS: We utilized PCa stem cells (PCSC), primary and metastatic PCa, intact and castrated Pten-/- mice, TRAMP mice, and xenografts produced in intact and castrated mice using LNCaP cells overexpressing empty vector (EV), PCSK9, gain-of-function (D374Y) and loss-of-function (Q152H) mutant. TRAMP/Pcsk9-/- mice were generated. The anti-PCSK9 antibody evolocumab was used. Androgen receptor (AR) signaling, angiogenesis, cholesterol accumulation, immune checkpoint (IC) expression, and CD8+ T cell infiltration were examined. RNA-seq was performed on xenografts. Differentially expressed genes and pathway alterations were evaluated.
RESULTS: PCSK9 upregulation occurs in PCSC, intact and castrated prostate-specific Pten-/- mice, primary, metastatic, and castration resistant PCa (CRPC). PCSK9 increased LNCaP tumor growth under intact and castrated conditions, and elevated intratumoral cholesterol, angiogenesis, nuclear AR, CYP17A1, and SRD5A1. Evolocumab treatment extended overall survival (OS) in TRAMP mice. TRAMP;Pcsk9-/- mice exhibited reduced tumor growth, metastasis, intratumoral cholesterol, CYP17A1, SRD5A1, ABI3, CORO1A, VISTA, CD53, enhanced CD8+ T cell infiltration and OS. ABI3, CORO1A, and CD53 are novel to PCa. ABI3 and CORO1A strongly correlate with CD53, VISTA, and multiple other ICs (n = 18) in 8 independent PCa populations, including metastases and CRPCs. ABI3 and CORO1A are among 15 immune-related genes (Sig15IM) upregulated by PCSK9. Sig15IM robustly stratifies PCa recurrence. In multiple single-cell RNA-seq datasets, Sig15IM, ABI3, ABI3corrgenes (ABI3 correlated genes), CORO1A, CORO1Acorrgenes, and CD53 are predominantly expressed or upregulated in exhausted CD8+ T and Treg in PCa and eight other cancer types.
CONCLUSIONS: PCSK9 promotes PCa progression via enhancing intratumoral cholesterol accumulation and shaping immunosuppressive microenvironment involving novel immunosuppressive factors: Sig15IM, ABI3, CORO1A, ABI3corrgenes, CORO1Acorrgenes, and CD53. PCSK9 facilitates VISTA expression in PCa.

Keywords:  Biomarkers; Immune evasion; PCSK9; Prostate cancer; castration-resistant prostate cancer (CRPC)

DOI:  https://doi.org/10.1016/j.jare.2026.04.020
Front Med (Lausanne). 2026 ;13 1807470

Therapy-induced androgen receptor signaling as a candidate upstream driver of B7-H3-linked immune exclusion in melanoma: mechanisms and translational opportunities.

Adrian P Mansini, John R Hyngstrom, Kyle T Amber.

  Melanoma frequently develops resistance to BRAF/MEK-targeted therapy and immune checkpoint blockade (ICB), often through therapy-driven tumor state transitions that include immune exclusion, transcriptional plasticity, and microenvironmental remodeling. B7-H3 (CD276) has been linked to immune-cold states and is being pursued as a therapeutic target. Yet, the upstream regulators that promote or stabilize B7-H3 immune exclusion in melanoma remain incompletely defined. Here, we propose a testable framework in which therapeutic pressure increases tumor-intrinsic androgen receptor (AR) signaling, which may promote or reinforce a B7-H3-linked immune-excluded resistance program. As a hypothesis-generating human anchor, in melanoma patients treated with anti-CTLA-4, AR and B7-H3 show no pre-treatment association, but a positive association emerges post-treatment. To avoid over-reliance on melanoma-specific preliminary observations, we integrate mechanistic precedent from other tumor contexts in which B7-H3 expression is shaped by defined signaling and epigenetic programs, including reported AR binding proximal to B7-H3 in prostate cancer and upstream control by stress- and growth-factor pathways. We then outline falsifiable mechanisms by which AR could interact with these regulatory nodes to increase B7-H3 output and barrier-like immune exclusion, and we highlight translational opportunities to therapeutically disrupt the AR-B7-H3 axis through modulation of the AR pathway and/or B7-H3-directed agents. This Perspective defines near-term experiments and study designs to validate directionality, delineate the relevant resistant tumor states, and establish a rational basis for combination therapy.

Keywords:  B7-H3 (CD276); BRAF/MEK inhibitors; androgen receptor (AR); immune checkpoint blockade; immune exclusion; melanoma; therapy resistance

DOI:  https://doi.org/10.3389/fmed.2026.1807470
Prostate Cancer. 2026 ;2026 4321914

The Impact of Tumor Microenvironmental Acidity on Bicalutamide Sensitivity in Prostate Cancer Cells.

Pedram Golmohammadi, Idris Haghani, Iman Menbari Oskouie, Rahil Mashhadi, Ahmadreza Rezaeian, Seyed Mohammad Kazem Aghamir.

   Background: Prostate cancer is the second most commonly diagnosed cancer worldwide. Although androgen deprivation therapy initially demonstrates clinical benefit, disease relapse with more aggressive phenotypes frequently occurs. The acidic tumor microenvironment in solid tumors may alter drug responsiveness. This study investigates how extracellular pH influences the cytotoxic effects of bicalutamide in human prostate cancer cell lines.
Methods: PC3 and LNCaP cells were exposed to bicalutamide at varying concentrations at pH 7.4 and pH 6.8. IC50 values were determined using the MTT assay. Cell migration, apoptosis, and cell cycle distribution were evaluated by wound-healing assay, annexin V/PI staining, and DNA content analysis, respectively. The expression of BAX, BCL2, E-cadherin, N-cadherin, SNAI1, AR, and VEGF-C was quantified by qPCR.
Results: Bicalutamide (140 μg/mL) reduced PC3 cell viability to 39.62% at pH 7.4 compared with 51.36% at pH 6.8. In LNCaP cells, viability declined to 33.64% at pH 7.4% and 56.09% at pH 6.8. Treated PC3 cells exhibited significantly greater migration at pH 6.8 (p < 0.01). Early apoptosis in treated LNCaP cells was significantly reduced at pH 6.8 (p < 0.001). Both cell lines demonstrated enhanced S phase accumulation and reduced G1-phase distribution at pH 6.8. The BAX/BCL2 ratio was significantly decreased at pH 6.8, indicating the suppression of proapoptotic signaling. Additionally, genes associated with epithelial-mesenchymal transition (EMT) were upregulated, and VEGF-C and AR expression increased at pH 6.8 (p < 0.05).
Conclusion: The efficacy of bicalutamide in prostate cancer cells is significantly influenced by extracellular pH. The drug exerts stronger cytotoxic, antimigratory, and proapoptotic effects at physiological pH (7.4) compared with acidic conditions (6.8).

Keywords:  acidic; androgen deprivation; bicalutamide; neutral; pH; prostate cancer

DOI:  https://doi.org/10.1155/proc/4321914
Adv Sci (Weinh). 2026 Apr 07. e20109

Androgen Receptor-Induced Lactoferrin Accelerates Prostate Tumorigenesis Through Modulating Ferroptosis.

Can Liu, Qiu Peng, Xiaoyue Zhang, Zhengshuo Li, Yangge Wu, Yuqing Wen, Run Zheng, Shuanglong Wu, Chenfei Zhou, Zhengyu Hu, Lanjun Shu, Xinyi Ma, Qiuyang Li, Ya Ma, Chunlin Ou, Ming Zhao, Songqing Fan, Lingyu Wei, Jian Ma.

  Lactoferrin (LF), an innate immunity molecule, showed a strikingly high expression level in the human prostate compared to other tissues and organs, indicating a significant role in prostate physiology. Despite the tumor-suppressive role of lactoferrin established in other malignancies, we reveal its paradoxical oncogenic function in prostate cancer through an androgen receptor (AR)-LF-ferroptosis axis. Utilizing Lf -/- TRAMP genetic mouse models, proteomics, TCGA-PARD data, and single-cell RNA-seq, we demonstrate that AR directly binds the LF promoter, driving LF expression, which in turn upregulates ferritin (FTH1/FTL) expression and suppresses p53-ALOX12-mediated ferroptosis in prostate cancer. Crucially, Lf deficiency delayed tumor progression and intensified ferroptotic stress in the TRAMP mice, while iron supplementation accelerated carcinogenesis-effects rescued by Lf knockout. Mechanistically, lactoferrin shields prostate cancer cells from iron-induced ferroptosis by maintaining iron-redox homeostasis. Preclinical targeting of this axis suggested a potential therapeutic strategy, as suppressed tumor growth in prostate cancer xenograft was observed following LF knockdown coupled with ferroptosis induction (via IKE) and androgen receptor inhibition (via enzalutamide). This work defines lactoferrin as: (i) an AR-regulated ferroptosis suppressor, (ii) a regulator of prostate cancer's "iron addiction," and (iii) a candidate target for therapeutic exploitation of iron-metabolic vulnerability.

Keywords:  TRAMP mouse model; androgen receptor; ferroptosis; lactoferrin; prostate cancer

DOI:  https://doi.org/10.1002/advs.202520109
Biochim Biophys Acta Rev Cancer. 2026 Apr 07. pii: S0304-419X(26)00058-2. [Epub ahead of print] 189586

Mapping the immune landscape of PCa: From tumor microenvironment to therapeutics.

Shanhe Huang, Yuan Ou, Wei Zhuang, Jinxing Huang, Baojun Wang, Zean Li, Hai Huang.

  Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, yet its response to immunotherapy is notably limited compared to other solid tumors. This resistance stems primarily from a highly immunosuppressive tumor microenvironment (TME), characterized by "cold" tumor features such as low mutational burden, scarce cytotoxic T cell infiltration and extensive regulatory cell populations. Building upon the "tumor ecosystem" concept, we integrate emerging insights from single-cell and spatial transcriptomics to decode the spatiotemporal heterogeneity of the PCa ecosystem. We specifically highlight the underappreciated "neural-immune-microbiome" axis-a triangular regulatory network wherein sympathetic nerves suppress T cell motility, intratumoral microbiota drive chronic inflammation, and metabolic reprogramming creates lipid-mediated immune paralysis. We further dissect how cell-type specific remodeling mechanisms, particularly TREM2+ macrophage-mediated metabolic symbiosis, drive the transition from hormone-sensitive to castration-resistant disease. Furthermore, we critically assess how standard of care (ADT, chemotherapy, radiotherapy) and emerging agents (PARPi, HDACi) reprogram the immune landscape with time-dependent, often paradoxical effects. Finally, we propose a roadmap for precision oncology, emphasizing that future success lies in "ecological editing"-biomarker-driven patient stratification and rational combination strategies to overcome the physical and biological barriers of the TME.

Keywords:  Immunotherapy; Metabolic reprogramming; Neuro-immune crosstalk; Prostate cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189586
Oncotarget. 2026 Mar 31. 17(1): 157-172

Epigenetic dysregulation and biological function of PDX1 in prostate cancer.

Tayo A Adeyika, Anju Datturgi, Yehnara Ettinoffe, Somiranjan Ghosh, Christopher Albanese, Bernard Kwabi-Addo.

  Copyright: © 2026 Adeyika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aberrant DNA methylation changes lead to abnormal gene expression that contributes to the development and progression of prostate cancer (PCa). Inquiry of genome-wide DNA methylation dataset, we identified the homeodomain pancreatic and duodenal homeobox 1 (PDX1) gene as differentially hypermethylated in PCa compared to normal prostate tissues. Immunohistochemical analysis of matched PCa and normal prostate tissues using tissue microarray showed a significant 2.33-fold (p = 0.0001) higher PDX1 protein expression in the PCa compared to the normal prostate tissues. In PCa cell lines (PC-3 and LNCaP) engineered to stably overexpress or knockdown PDX1, the ectopic PDX1 expression significantly enhanced cell proliferation and migration, whereas PDX1 knockdown suppressed these phenotypic processes. Quantitative RT-PCR and Western blot analysis demonstrated that PDX1 overexpression was associated with increased expression of key metabolic regulators; INSR, IGF1R, CXCR4, CDH2, TWIST1, and SNAI1, whereas there is decreased expression of ESR2, and TNFα. Conversely, PDX1 knockdown led to the opposite effect in expression profiles of these metabolites. Notably, these effects were more pronounced under high-glucose conditions compared to low-glucose environments. Overall, our findings suggest that PDX1 plays a tumor-promoting role in human PCa cells by influencing expression of metabolites in insulin, inflammatory, and epithelial-mesenchymal transition (EMT) signaling pathways. Given its potential role in metabolic regulation, full insights into the function of PDX1 in PCa could contribute to improved treatment and prevention strategies, particularly for men with PCa and comorbidities such as obesity and diabetes.

Keywords:  DNA methylation prostate cancer; PDX1; glucose; over-expression; shRNA knockdown

DOI:  https://doi.org/10.18632/oncotarget.28854
Cell Death Dis. 2026 Apr 10.

Mechanism and therapeutic significance of ARV-110 combined with a PDGFR inhibitor for the induction of apoptosis in castration-resistant prostate cancer cells through the ROS/JNK pathway.

Yang Fu, Shanshan Sun, Guangxu Liu, Qingzhuo Dong, Yutao Wang, Haoyuan Zheng, Chiyuan Piao, Jianbin Bi.

The clinical treatment of castration-resistant prostate cancer (CRPC) is currently a major challenge. This study explored a new combination strategy for CRPC that targeted androgen receptor (AR)-dependent and AR-independent mechanisms. First, the degradation efficiency of AR by ARV-110 was verified. CCK-8 and CellTiter-Glo assays were used to evaluate the viability of CRPC cells after treatment. The combination index of platelet-derived growth factor receptor (PDGFR) inhibitors combined with ARV-110 was calculated using CompuSyn software. Transcriptome sequencing was used to explore the in-depth mechanisms of the combination strategy. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to clarify the transcriptional regulatory relationships. Coimmunoprecipitation was used to evaluate protein interactions. The results showed that ARV-110 significantly promoted AR degradation. The combination of ARV-110 and ponatinib exerted a significant inhibitory and synergistic effect on CRPC cells. The effective targets were AR and PDGFR. The combination of ARV-110 and the PDGFR-selective inhibitor JNJ10198409 effectively induced the apoptosis of CRPC cells. ARV-110 alone promoted the transcription of PDGFA. And the combination strategy further induced JNK signaling pathway activation and promoted cell apoptosis by inhibiting PDGFR activity. Additionally, the substantial accumulation of reactive oxygen species induced by the combination strategy was related to the joint downregulation of catalase by the two drugs through different mechanisms. In conclusion, this study described a new strategy for the treatment of CRPC and clarified the molecular mechanisms of the combination strategy, providing a new theoretical basis for the precision treatment of CRPC.

DOI: https://doi.org/10.1038/s41419-026-08718-w
STAR Protoc. 2026 Apr 07. pii: S2666-1667(26)00139-5. [Epub ahead of print]7(2): 104486

Protocol for generating and characterizing Matrigel-free prostate cancer patient-derived organoids.

Robin Dolgos, Romuald Parmentier, Jing Wang, Arnoud J Templeton, Kirsten D Mertz, Heike Pueschel, Helge Seifert, Ashkan Mortezavi, Tatjana Vlajnic, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen.

  Here, we present a protocol for the generation of prostate cancer patient-derived organoids (PCa PDOs) in Matrigel-free conditions. We describe steps for sample selection, pathological resection, and tissue dissociation. We then detail procedures for the generation, maintenance, and characterization of the PCa PDOs. Finally, we provide guidance for the processing of PDOs for single-cell RNA sequencing (scRNA-seq) analysis and using the prostate PDO single-cell atlas (PPScA) for both novice and advanced bioinformatic users. For complete details on the use and execution of this protocol, please refer to Dolgos et al.1.

Keywords:  Bioinformatics; Cancer; Cell Biology; Molecular Biology; Organoids

DOI:  https://doi.org/10.1016/j.xpro.2026.104486
Phytomedicine. 2026 Apr 04. pii: S0944-7113(26)00392-2. [Epub ahead of print]155 158158

Astragaloside IV directly targets PPP1R14B to sensitize prostate cancer to anti-PD-1 immunotherapy by remodeling the CX3CL1/CD8+ T cell axis.

Jie Yang, Jia Wang, Wenbo Zhang, Han He, Chao Wang, Yunfeng Zhang, Fenghai Zhou.

   BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) in prostate cancer (PCa) is driven by a "cold" tumor immune microenvironment. Astragaloside IV (AS-IV), a major bioactive saponin isolated from Astragalus membranaceus, exhibits immunomodulatory potential, yet its direct molecular targets remain elusive. Concurrently, PPP1R14B is overexpressed in PCa, but its role in mediating immune evasion is unclear.
PURPOSE: To investigate whether AS-IV targets PPP1R14B to remodel the tumor immune microenvironment (TIME) and sensitize PCa to anti-PD-1 therapy.
METHODS: The AS-IV/PPP1R14B interaction was validated using molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assays (CETSA). Mechanisms were dissected via ubiquitination assays, ROS analysis, and T cell co-cultures. Antitumor efficacy was evaluated in syngeneic mouse models alone or with anti-PD-1.
RESULTS: AS-IV bound PPP1R14B (KD = 4.88 μM), inducing its ubiquitin-proteasomal degradation. This depletion inhibited Wnt/β-catenin signaling via regulation of the AKT/GSK-3β axis and induction of mitochondrial ROS. Consequently, AS-IV relieved CX3CL1 repression, promoting the recruitment and cytotoxic function of CD8+ T cells. In vivo, AS-IV synergized with anti-PD-1 to suppress tumor growth, an effect that was largely dependent on PPP1R14B downregulation.
CONCLUSION: AS-IV reverses immune exclusion by targeting PPP1R14B to suppress Wnt/β-catenin signaling. These findings identify the AS-IV/PPP1R14B/CX3CL1 axis as a mechanistic basis for using AS-IV to overcome ICI resistance in PCa.

Keywords:  Astragaloside IV; CX3CL1; Immune exclusion; PPP1R14B; Prostate cancer; Wnt/β-catenin signaling

DOI:  https://doi.org/10.1016/j.phymed.2026.158158
Clin Transl Oncol. 2026 Apr 10.

Androgen receptor pathway inhibitor intensification in non-metastatic hormone-sensitive prostate cancer: current evidence and clinical implications.

Patricia Willisch, Beatriz Vázquez-Barreiro, Ana Plata, Irene Cienfuegos Belmonte, Gloria Guardia, Rocío Del Castillo-Acuña, Giulio Francolini, Ciro Franzese, José Daniel Subiela Henríquez, Felipe Couñago, Fernando López-Campos.

  Prostate cancer is the most common malignancy in men. Although frequently diagnosed at localized stages, a substantial proportion present high-risk features associated with biochemical recurrence and progression. In non-metastatic hormone-sensitive prostate cancer (nmHSPC), standard treatment has traditionally consisted of local therapy combined with androgen deprivation therapy (ADT), but recent advances have reshaped the therapeutic landscape. The addition of androgen receptor pathway inhibitors (ARPIs) to ADT has demonstrated substantial survival benefits in metastatic hormone-sensitive disease, providing the rationale for exploring treatment intensification in earlier stages. Modern imaging techniques, particularly PSMA PET, enable detection of occult metastatic disease influencing treatment selection. Emerging evidence from randomized and phase II-III studies suggests that ARPI intensification combined with radiotherapy, surgery, or salvage approaches may improve disease control in selected high-risk nmHSPC populations. This narrative review summarizes the evidence supporting ARPI intensification in nmHSPC and discusses the clinical implications of recent advances.

Keywords:  Androgen deprivation therapy (ADT); Androgen receptor pathway inhibitors (ARPI); Non-metastatic hormone-sensitive prostate cancer (nmHSPC); PSMA PET; Radiotherapy (RT)

DOI:  https://doi.org/10.1007/s12094-026-04350-4
Cureus. 2026 Mar;18(3): e104755

A Shot in the Dark: Unprecedented Complete Radiologic Response of Metastatic Prostate Cancer to Single-Dose Androgen Deprivation Therapy (ADT).

Rohit S Deshpande, Puneet Ahluwalia.

  Androgen deprivation therapy (ADT) is a well-established treatment strategy for metastatic prostate cancer, aimed at reducing tumor burden and alleviating symptoms. Although ADT is a cornerstone in managing prostate cancer, complete radiological regression of metastatic disease, with a single dose of ADT, has not been previously reported. We present an exceptional case of a patient with metastatic prostate cancer who achieved a complete radiological response to ADT, highlighting an extraordinary therapeutic outcome.

Keywords:  androgen deprivation therapy; metastatic; prostate cancer; psa; psma-pet-ct

DOI:  https://doi.org/10.7759/cureus.104755
Med Res Rev. 2026 Apr 07.

Urologic Bacteriome: The Hero or the Villain in Prostate Cancer Onset, Progression, and Treatment?

Lara R S Fonseca, Mariana Feijó, Cátia V Vaz, Bruno J Pereira, Sandra Laurentino, Ana Palmeira-de-Oliveira, Sílvia Socorro.

  Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide and the fifth leading cause of cancer-related mortality, presenting urgent unmet clinical needs in diagnosis and treatment. The recognition of the microbiome as a key factor in human health has prompted numerous studies, revealing an exciting new approach to cancer diagnosis and therapy. The bacteriome is the component of the microbiome that is most metabolically active and influenceable by internal and external factors, which is pivotal in the development of cancer. Initial studies exploring the link between the microbiome and PCa focused primarily on the gut bacteriome, which has been implicated in the onset and progression of the disease, as well as in resistance to therapy. Further research has demonstrated that the urologic bacteriome also plays a crucial role in the development of PCa, serving as an important factor for diagnosis and treatment. This review synthesizes current knowledge concerning the significance of the urologic bacteriome in PCa onset, progression, diagnosis/prognosis, and therapy. It also explores the impact of the bacterial metabolome in PCa, emphasizing the importance of this undervalued dimension of the bacteriome. Overall, the review provides a comprehensive analysis of how bacteria and their bioactive metabolites contribute to PCa, highlighting their clinical and therapeutic relevance. It also identifies the existing knowledge gaps, paving the way for the development of new approaches that could enhance PCa diagnosis and treatment.

Keywords:  bacteria metabolome; bacterial metabolites; bacterial toxins; prostate cancer; urologic bacteriome

DOI:  https://doi.org/10.1002/med.70042