ArticleJournal of translational medicine2025
DAPK1-positve macrophages facilitate immunosuppressive microenvironment and determine immunotherapy efficacy in colorectal cancer.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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10 authors.
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Abstract
backgroundColorectal cancer (CRC) is a highly immunosuppressive malignancy characterized by limited therapeutic options and a poor prognosis. Within the CRC tumor immune microenvironment (TIME), tumor-associated macrophages (TAMs) represent the predominant immune cell population. This study aimed to characterize the specific macrophage subsets contributing to CRC progression and resistance to immunotherapy.
methodsSingle-cell RNA sequencing (scRNA-seq) was used to identify the key macrophage marker genes. The clinical significance of death-associated protein kinase 1 (DAPK1), was evaluated in clinical CRC cohorts using immunohistochemistry, immunofluorescence, Kaplan-Meier plots and Cox Proportional Hazards Models. Cytometry by time-of-flight, RNA-seq, flow cytometry and an in vitro co-culture system were performed to explore the functional role of macrophage-derived DAPK1 in the TIME. Subcutaneous tumor models and splenic-liver metastasis models were constructed to assess the potential of DAPK1 inhibition to enhance immune checkpoint blockade (ICB) efficacy.
resultsscRNA-seq analysis revealed predominant DAPK1 expression in intratumoral macrophages of CRC TIME. Elevated macrophage-specific DAPK1 level was significantly associated with worse prognosis. DAPK1+TAMs exhibited immunosuppressive properties and inhibit CD8+T cells cytotoxicity. Pharmacological inhibition of DAPK1 enhanced the efficacy of anti-PD-1 therapy in murine models.
conclusionsDAPK1+TAMs infiltration was an independent risk factor for overall survival in patients with CRC. These DAPK1+TAMs exhibit an immunosuppressive phenotype and promote the establishment of the TIME with immune evasion. Targeting DAPK1 may represent a potential strategy for synergizing immunotherapy in CRC treatment.
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