ONCOLOGY REPORTS 56 - Decoding the metabolic-immune crosstalk: The role of glutamine and ammonium reprogramming in prostate cancer immune evasion (Review)

Sep 22, 2026

Prostate cancer progression is driven by metabolic reprogramming and immune evasion, yet their interface remains incompletely defined. Dysregulated glutamine metabolism reshapes antitumor immunity via nutrient competition and ammonium accumulation in the tumor microenvironment. Ammonium acts as an immunosuppressive metabolite, impairing T cell function and promoting macrophage M2 polarization. This review summarizes bidirectional metabolic-immune crosstalk, highlighting glutamine-ammonium as a promising but largely untapped therapeutic target for clinical translation and combination with immunotherapy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Glutamine metabolism in PCa: Mechanisms and regulation

Ammonium metabolism

Metabolic reprogramming of immune cells in the prostate TME

Bidirectional metabolic-immune crosstalk: Glutamine and ammonium as key mediators

Therapeutic strategies targeting the metabolic-immune interface

Future perspectives

Conclusion

ONCOLOGY REPORTS 56: 180, 2026 Decoding the metabolic‑immune crosstalk: The role of glutamine and ammonium reprogramming in prostate cancer immune evasion (Review) PEILONG WANG 1‑3 , XIAORAN LI 1‑3 , TENG MA 1‑3 and JUN MI 1‑3 1 Department of Urology, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China; Institute of Urology, Gansu Nephro‑Urological Clinical Center, Lanzhou, Gansu 730030, P.R. China; 2 3 Key Laboratory of Urological Diseases in Gansu Province, Lanzhou, Gansu 730030, P.R. China Received March 12, 2026; Accepted July 29, 2026 DOI: 10. 3892/or.2026.9186 Abstract. Prostate cancer progression is typically driven by metabolic reprogramming and immune evasion, yet the inter‑ face between these processes remains incompletely understood. Dysregulated glutamine metabolism extends beyond bioener‑ getic support to actively shape antitumor immunity through nutrient competition and ammonium accumulation within the tumor microenvironment. Ammonium, traditionally viewed asa toxic waste product, is a critical immunosuppressive metabo‑ lite that impairs T cell function and promotes macrophage M2 polarization. The present review aimed to summarize the bidi‑ rectional crosstalk between tumor metabolism and immune cells, with emphasis on how metabolic alterations drive thera‑ peutic resistance. While the majority of evidence supporting this axis derives from preclinical models, the present review highlights the glutamine‑ammonium axis as a promising but largely untapped therapeutic target requiring translation into clinical investigation, including combination strategies with immunotherapy. Contents 1. Introduction 2. Glutamine metabolism in PCa: Mechanisms and regulation 3. Ammonium metabolism 4. Metabolic reprogramming of immune cells in the prostate TME Correspondence to: Professor Jun Mi, Department of Urology, Lanzhou University Second Hospital, 80 Cuiying Men Street, Cheng‑guan, Lanzhou, Gansu 730030, P.R. China E‑[mail: mj7690@163.com](mail: mj7690@163.com) Key words: glutamine metabolism, ammonium, prostate cancer, immune evasion, tumor microenvironment, metabolic reprogramming, immunometabolism, therapeutic target 5. Bidirectional metabolic‑immune crosstalk: Glutamine and ammonium as key mediators 6. Therapeutic strategies targeting the metabolic‑immune interface 7. Future perspectives 8. Conclusion 1. Introduction Prostate cancer (PCa) is a leading cause of cancer‑related morbidity and mortality among male patients worldwide, with recent estimates indicating ~1.4 million new cases and 375,000 deaths annually (1) . Despite advances in early detection and treatment, a substantial proportion of patients (10‑20% within 5 years) develop castration‑resistant PCa (CRPCa), a lethal disease state characterized by therapeutic resistance and poor clinical outcomes (2) . Comprehensive genomic analysis has revealed that advanced PCa involves complex molecular alterations that influence disease progression and treatment response (3) . Among these, androgen receptor splice variant 7 (AR‑V7) has been prospectively validated as a predictive biomarker of resistance to hormone therapy in high‑risk patients (4) . Furthermore, distinct genomic drivers associated with enzalutamide resistance have been identified in metastatic CRPCa, highlighting the heterogeneous and adaptive nature of treatment failure (5) . The biological evolution from hormone‑sensitive to CR disease involves not only genomic alterations but also meta‑ bolic reprogramming (6) . This metabolic rewiring enables tumor cells to sustain proliferation under therapeutic pressure and nutrient‑limited conditions (7) . Concurrently, the tumor microenvironment (TME) undergoes notable remodeling that promotes immune evasion, with evidence indicating that meta‑ bolic alterations directly influence immune cell function (8) . The recognition that metabolic reprogramming and immune evasion are interconnected rather than in

FAQs

How does dysregulated glutamine metabolism influence antitumor immunity in prostate cancer?

It extends beyond energy supply to actively shape antitumor immunity through nutrient competition and ammonium accumulation within the tumor microenvironment.

What immunological effects does ammonium have in the prostate tumor microenvironment?

Ammonium impairs T cell function and promotes macrophage M2 polarization, acting as a critical immunosuppressive metabolite.

Why is the glutamine-ammonium axis considered a therapeutic target, and what is needed next?

Preclinical evidence supports targeting this metabolic-immune interface, but clinical translation is largely lacking; the review emphasizes combination strategies with immunotherapy and further clinical investigation.

Sep 22, 2026

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