Targeting PLD3 Reverses the Immunosuppressive Niche by Reprogramming Tumor-Associated Macrophages and Potentiates...

Area of Science:

• Oncology
• Immunology
• Macrophage Biology

Background:

• Colorectal cancer (CRC) with mismatch repair-proficient/microsatellite stable (MSS) status often resists immune checkpoint inhibitors (ICIs).
• Tumor-associated macrophages (TAMs) are critical mediators of this resistance.
• Phospholipase D3 (PLD3), expressed in macrophages, impacts immunotherapy efficacy and patient outcomes.

Purpose of the Study:

• To elucidate PLD3's role in macrophage phenotype, CRC progression, and immunotherapy response.
• To identify agents targeting PLD3 for therapeutic intervention.

Main Methods:

• Immunofluorescence for spatial infiltration dynamics.
• Myeloid-specific Pld3-knockout mouse models.
• Single-cell RNA sequencing (scRNA-seq) and flow cytometry for TME analysis.
• RNA sequencing (RNA-seq) and mass spectrometry for molecular exploration.
• Molecular docking and tumor models for therapeutic assessment.

Main Results:

• PLD3+ macrophages spatially dictate immunotherapy resistance in CRC.
• PLD3 modulates the lysosomal-AKT-NF-κB axis, inducing macrophage senescence and an anti-inflammatory phenotype.
• This leads to suppressed NK and T cell function, creating an immunosuppressive TME.
• Abrine, a PLD3 inhibitor, demonstrated potential in enhancing immunotherapy response.

Conclusions:

• PLD3 promotes CRC progression and ICI resistance by driving macrophage senescence and immunosuppression.
• Targeting macrophage-specific PLD3 presents a viable strategy to overcome immunotherapy resistance in MSS CRC.
• Abrine shows promise as a therapeutic agent to enhance anti-tumor immunity.