TY - EJOU
AU - Zhang, Yangyang
AU - Mamtili, Ilyar
AU - Chen, Yonghao
AU - Ji, Guangjie
AU - Liang, Chaozhao
TI - PRDM1 Drives a TIM3+ Macrophage Immunosuppressive Niche via LGALS9 Signaling in Prostate Cancer Progression
T2 - Oncology Research
PY -
VL -
IS -
SN - 1555-3906
AB - Background: Prostate cancer (PCa) responds poorly to immunotherapy. We investigated the myeloid checkpoint TIM3 (HAVCR2) to define its lineage localization and regulatory logic in the PCa microenvironment. Methods: We integrated stage-resolved public single-cell RNA-seq datasets spanning primary PCa, metastatic hormone-sensitive PCa, and castration-resistant PCa. Myeloid compartments were analyzed via differential expression, regulon inference, and ligand–receptor modeling. Clinical relevance was evaluated in the Cancer Genome Atlas prostate adenocarcinoma (TCGA-PRAD) cohort and independent cohorts using a myeloid TIM3 signature. Mechanistic validation was achieved through PR domain zinc finger protein 1 (PRDM1) chromatin immunoprecipitation followed by Chromatin Immunoprecipitation (ChIP)–qPCR (ChIP-qPCR), TIM3-promoter luciferase assays, and functional perturbation of the galectin 9 (LGALS9)-TIM3 signaling pathway in macrophages differentiated. Results: TIM3 expression was predominantly confined to monocytes/macrophages, indicating TIM3 as a microenvironmental checkpoint in PCa. TIM3_high macrophages formed a Secreted Phosphoprotein 1 (SPP1)-enriched tumor-associated macrophage (TAM) state coupled to chemokine programs and extracellular matrix remodeling. Regulon profiling nominated PR domain zinc finger protein 1 (PRDM1) as an upstream driver; PRDM1 correlated with TIM3. Communication inference further highlighted an LGALS9-TIM3 axis and a C-X-C motif chemokine receptor 4/integrin subunit beta 1 (CXCR4/ITGB1)-associated permissive niche. Recombinant LGALS9 induced TIM3-linked M2-like macrophages polarization and increased CXCR4/ITGB1, which was attenuated by TIM3 blockade. Conclusions: Our results delineate a PRDM1-licensed TIM3_high macrophage program sustained by an LGALS9-TIM3 reinforcement loop and coupled to immunosuppressive and remodeling-associated phenotypes. Targeting TIM3 in the myeloid compartment, alone or in rational combinations, may represent a feasible strategy to reprogram tumor-associated macrophage states in PCa.
KW - Prostate cancer; single-cell; macrophage; immunoregulator; disease subtyping
DO - 10.32604/or.2026.079316