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

Wenxue Huang1, Weijia Li1, Wentai Shangguan1,2

  • 1Nanfang Hospital, Southern Medical University, Guangzhou, 510000, China.

International Journal of Biological Sciences
|April 7, 2026
PubMed

Insights

Metabolic reprogramming of tumor-associated macrophages (TAMs) is key for treating urologic cancers. Targeting specific metabolic axes can convert "cold" tumor ecosystems into treatment-responsive states, enhancing immunotherapy efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Metabolic Research

Background:

  • Therapeutic response in urologic cancers depends on metabolic-immune interactions influencing tumor-associated macrophages (TAMs).
  • Myeloid-rich "cold" tumor environments impair immune responses and limit the effectiveness of immune-checkpoint inhibitors (ICIs).

Purpose of the Study:

  • To review key metabolic axes (lactate-pH/hypoxia-HIF-VEGF, lipid rafts, ferroptosis-redox) that regulate TAM phenotype and function in urologic cancers.
  • To outline pharmacodynamic biomarkers and preclinical models for translating metabolic insights into clinical strategies for enhancing ICI therapy.

Main Methods:

  • Review of literature on metabolic pathways influencing TAMs and their role in urologic cancer immunity.
  • Discussion of pharmacodynamic anchors including hyperpolarized 13C-pyruvate MRI, soluble ANGPT2, and spatial NT5E/ADORA2A.
  • Integration of organoid-immune co-cultures, humanized/xenograft systems, and ex vivo tumor slices for translational research.

Main Results:

  • The lactate-pH/hypoxia-HIF-VEGF axis promotes acidic, adenosinergic suppression and angiogenesis.
  • The lipid rafts axis stabilizes inhibitory signaling and impairs phagocytosis/antigen presentation.
  • The ferroptosis-redox axis modulates inflammatory versus tolerogenic TAM states.

Conclusions:

  • Metabolism-informed TAM re-education is a promising strategy to convert "cold" urologic tumors into ICI-responsive phenotypes.
  • Prioritizing tumors with high glycolysis or adenosine and rational sequencing with ICIs can optimize treatment outcomes.
  • This approach offers a path to improve therapeutic responsiveness in urologic cancers by modulating the tumor microenvironment.
Keywords:
Tumor-associated macrophagebladder cancermetabolic reprogrammingprostate cancerrenal cell carcinoma

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