@Article{or.2026.079316,
AUTHOR = {Yangyang Zhang, Ilyar Mamtili, Yonghao Chen, Guangjie Ji, Chaozhao Liang},
TITLE = {PRDM1 Drives a TIM3+ Macrophage Immunosuppressive Niche via LGALS9 Signaling in Prostate Cancer Progression},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/26824},
ISSN = {1555-3906},
ABSTRACT = {<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.},
DOI = {10.32604/or.2026.079316}
}