Metabolic–Immune Coupling in Urologic Cancers - Macrophage Reprogramming as a Therapeutic Nexus

Sep 22, 2026

Therapeutic responsiveness in urologic cancers is gated by metabolic–immune coupling that conditions tumor-associated macrophages (TAMs). Myeloid-dominated “cold” ecosystems blunt antigen handling, phagocytosis, and trafficking, limiting the benefit of immune-checkpoint inhibitors (ICIs). This review frames three metabolic axes shaping TAM state and niche: lactate–pH/hypoxia–HIF–VEGF, lipid rafts/inhibitory hubs, and ferroptosis–redox control of inflammatory versus tolerogenic set-points.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

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Introduction

Metabolic–immune coupling and urologic cancer immune responsiveness

Warburg effect, lactate, and hallmark TME features

Lipid and iron metabolism linking tumor and immune cell programs

TAM plasticity shaped by metabolic cues

Three high-value metabolic axes for TAM-centered therapeutic translation

Ivyspring International Publisher InternationalJournal of Biological Sciences 2026; 22(6): 3087-3107. doi: 10.7150/ijbs.127634 Review Metabolic–Immune Coupling in Urologic Cancers: Macrophage Reprogramming as a Therapeutic Nexus Wenxue Huang1,􀀍, Weijia Li1,􀀍, Wentai Shangguan1,3, Lin Yang1, Zhuohang Li1, Boyuan Sun1, Cunzhen Ma1, Xunguo Yang1, Peidan Peng1,􀀍, Jie Zhao4,􀀍, Bisheng Cheng1,2,􀀍, Peng Wu1,􀀍 1. Nanfang Hospital, Southern Medical University, Guangzhou, 510000, China. 2. Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School,Boston, MA, USA. 3. Department of Urology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. 4. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. \# These authors contributed equally to this work. 􀀍 Corresponding authors: Peidan Peng: [451532841@qq.com](451532841@qq.com), Jie Zhao: [zhaojie_0412@163.com](zhaojie_0412@163.com), Bisheng Cheng: [chengbsh@alumni.sysu.edu.cn](chengbsh@alumni.sysu.edu.cn), Peng Wu: [doctorwupeng@gmail.com](doctorwupeng@gmail.com). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.10.31; Accepted: 2026.02.13; Published: 2026.02.26 Abstract Therapeutic responsiveness in urologic cancers is gated by metabolic–immune coupling that conditions tumor-associated macrophages (TAMs). Myeloid-dominated “cold” ecosystems blunt antigen handling, phagocytosis, and trafficking, limiting the benefit of immune-checkpoint inhibitors (ICIs). This review focuses on three high-value axes that shape TAM state and niche: the lactate–pH / hypoxia–HIF–VEGF axis that enforces acidic, adenosinergic suppression and angiogenic programs; lipid rafts axis that stabilizes inhibitory hubs (e.g., PI3K–AKT/TREM2) and skews phagocytosis/antigen presentation; and ferroptosis– redox axis control that sets inflammatory versus tolerogenic set-points. The review further outlines pharmacodynamic anchors—hyperpolarized 13C-pyruvate MRI (kPL), soluble ANGPT2, and spatial NT5E/ADORA2A modules—to operationalize a bench-to-biomarker-to-bedside loop using organoid– immune co-cultures, humanized/xenograft systems, and ex vivo tumor slices. This framework prioritizes adaptive enrichment for glycolysis-or adenosine-high tumors, rational timing/sequencing with ICIs, and avoidance of global myelosuppression. Collectively, metabolism-informed TAM re-education offers a route to convert myeloid-dominated “cold” ecosystems into treatment-responsive states across urologic cancers. Keywords: Tumor-associated macrophage; metabolic reprogramming; prostate cancer; bladder cancer; renal cell carcinoma 1. Introduction Urologic malignancies, including prostate cancer (PCa), bladder cancer (BCa), and renal cell carcinoma (RCC), represent major contributors to global cancer incidence and mortality[1, 2] . Despite the remarkable success of ICIs across multiple cancer types, response rates remain highly variable between patients inurologic cancers[3] . A substantial fraction of tumors display an immune-excluded or non-inflamed microenvironment characterized by enrichment of immunosuppressive myeloid populations; these tumors less often benefit from immunotherapy[3] . Within this landscape, tumor-associated macrophages (TAMs) constitute a dominant and highly plastic myeloid compartment with a central role in shaping immune tone and treatment responsiveness. Macrophage states are not fixed but are continuously instructed by tumor- and microenvironment-derived cues[4] . Among these, tum

FAQs

Why do urologic cancers often show variable responses to immune-checkpoint inhibitors (ICIs)?

Responses vary because many tumors develop immune-excluded or non-inflamed microenvironments enriched with immunosuppressive myeloid populations. This limits the effectiveness of immunotherapy.

How does metabolic–immune coupling influence tumor-associated macrophages (TAMs)?

Metabolic rewiring reshapes the tumor microenvironment and drives immune-cell function. It conditions TAM plasticity and niche adaptation, biasing TAM programs toward immunosuppression.

What three metabolic axes does the review use to explain TAM state and therapeutic potential?

The review highlights the lactate–pH/hypoxia–HIF–VEGF axis, the lipid rafts axis stabilizing inhibitory hubs and altering phagocytosis/antigen presentation, and the ferroptosis–redox axis that sets inflammatory versus tolerogenic set-points.

Sep 22, 2026

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