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PRDM1 Drives a TIM3+ Macrophage Immunosuppressive Niche via LGALS9 Signaling in Prostate Cancer Progression
Yangyang Zhang1,2,3, Ilyar Mamtili4, Yonghao Chen5
1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Oncology Research
|June 26, 2026
Summary
The myeloid checkpoint TIM3 (T-cell immunoglobulin and mucin-domain containing-3) is a key regulator in prostate cancer (PCa) progression. Targeting TIM3 may reprogram immunosuppressive tumor-associated macrophages in PCa.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Prostate cancer (PCa) exhibits poor response to immunotherapy.
- The myeloid checkpoint TIM3 (HAVCR2) role in the PCa microenvironment remains undefined.
Purpose of the Study:
- Investigate TIM3 localization and regulatory mechanisms within the PCa microenvironment.
- Define TIM3's role in myeloid cell function and its clinical relevance.
Main Methods:
- Integrated single-cell RNA-seq data from primary and metastatic PCa.
- Analyzed myeloid compartments using differential expression, regulon inference, and ligand-receptor modeling.
- Validated findings using TCGA-PRAD cohort, ChIP-qPCR, luciferase assays, and functional perturbation of the LGALS9-TIM3 pathway.
Main Results:
- TIM3 expression is primarily restricted to monocytes/macrophages in PCa.
- TIM3_high macrophages exhibit an SPP1-enriched TAM state associated with immunosuppression and ECM remodeling.
- Identified PRDM1 as an upstream driver of TIM3 and highlighted an LGALS9-TIM3 axis and CXCR4/ITGB1 signaling.
Conclusions:
- A PRDM1-driven TIM3_high macrophage program sustains immunosuppressive and remodeling phenotypes in PCa.
- The LGALS9-TIM3 axis reinforces this program.
- Targeting TIM3 in myeloid cells offers a potential strategy to reprogram TAMs and enhance PCa immunotherapy.
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