2. Academic Validation
  3. DAPK1-positve macrophages facilitate immunosuppressive microenvironment and determine immunotherapy efficacy in colorectal cancer

DAPK1-positve macrophages facilitate immunosuppressive microenvironment and determine immunotherapy efficacy in colorectal cancer

  • J Transl Med. 2025 Nov 4;23(1):1220. doi: 10.1186/s12967-025-07268-7.
Jiang Chang # 1,  Yuxu Niu # 2,  Shizhao Zhou # 1,  Ziqi Zhang # 3 4,  Weiying Zhu 1,  Junchang Zhu 1,  Haoran Xiu 1,  Ke Shang 1,  Qingyang Feng 5 6,  Ye Wei 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
  • 2 Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Colorectal Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Technology, Shanghai, China.
  • 5 Colorectal Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 6 Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Technology, Shanghai, China. [email protected].
  • 7 Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41188869 DOI: 10.1186/s12967-025-07268-7
Abstract

Background: Colorectal 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.

Methods: Single-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.

Results: scRNA-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.

Conclusions: DAPK1+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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-07268-7.

Keywords

Cancer immunotherapy; Death-associated protein kinase; Tumor immune microenvironment; Tumor-associated macrophage.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15513
    DAPK Inhibitor