Related Experiment Video
Updated: Aug 14, 2025
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate
Jun Xiao1,2,3, Fei Sun3, Ya-Nan Wang1,3
1Department of Urology.
Abstract:
The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.
Insights
Targeting UBC9 in prostate cancer (PCa) reverses immunosuppressive tumor-associated macrophages (TAMs) by enhancing STAT4 activation and CD8+ T cell responses. This approach offers a novel strategy to combat PCa progression.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The role of tumor-associated macrophages (TAMs) and their activation states in prostate cancer (PCa) is not fully understood.
- Understanding macrophage regulation is crucial for developing effective PCa therapies.
Purpose of the Study:
- To investigate the role of UBC9 in regulating macrophage activation and antitumor immunity in prostate cancer.
- To explore UBC9 as a therapeutic target for PCa.
Main Methods:
- Utilized a mouse model with macrophage-specific Ubc9 deficiency to study PCa growth.
- Performed biochemical and molecular analyses to identify UBC9-mediated targets, including STAT4 SUMOylation.
- Administered a UBC9 inhibitor (2-D08) and assessed its effects on TAMs and CD8+ T cells, in combination with immune checkpoint blockade.
Main Results:
- PCa growth was suppressed in mice with Ubc9-deficient macrophages, linked to enhanced CD8+ T cell responses.
- STAT4 was identified as a key UBC9-mediated SUMOylation target, with K350 being the primary modification site.
- UBC9 inhibition (2-D08) promoted antitumor effects of TAMs and increased PD-1 expression on CD8+ T cells, showing synergistic efficacy with immune checkpoint blockade.
Conclusions:
- UBC9 ablation reverses the immunosuppressive phenotype of TAMs by promoting STAT4-mediated activation and macrophage-CD8+ T cell crosstalk.
- Targeting UBC9 presents a promising strategy to enhance antitumor immunity in prostate cancer.
- These findings offer valuable insights for halting PCa tumorigenesis through immune modulation.
