Reprogramming Tumor-Associated Macrophages via Targeted NAT10 Inhibition to Enhance Colorectal Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Colorectal cancer (CRC) remains a significant health challenge.
• Current immunotherapies face limitations in efficacy and targeting.
• Macrophages play a crucial role in the tumor microenvironment, with M2-phenotype macrophages often promoting tumor growth.

Purpose of the Study:

• To develop and evaluate a novel nanorobot, Sono@NAT10, for targeted immunotherapy in colorectal cancer.
• To investigate the mechanism by which Sono@NAT10 modulates macrophage phenotype.
• To assess the therapeutic efficacy of Sono@NAT10 in combination with anti-PD-1 therapy in a CRC mouse model.

Main Methods:

• Fabrication of Sono@NAT10 using metal-organic framework and macrophage membrane.
• Ultrasound-triggered release of NAT10 siRNA.
• Flow cytometry and confocal imaging for macrophage targeting assessment.
• RNA sequencing and proteomics to identify molecular targets and pathways.
• Evaluation of tumor growth inhibition and survival in a CRC mouse model.

Main Results:

• Sono@NAT10 demonstrated stability and effective targeting of macrophages.
• NAT10 siRNA delivery induced a phenotypic switch of macrophages from M2 to M1.
• NAT10 was found to regulate SRSF2 protein stability, mediating the M2-to-M1 transition.
• Combination therapy of Sono@NAT10 and anti-PD-1 antibody significantly inhibited tumor growth and improved survival in CRC mice.

Conclusions:

• Sono@NAT10 is a promising nanorobot for CRC immunotherapy by modulating macrophage polarization via NAT10.
• Targeting NAT10 phase separation offers a novel strategy for cancer treatment.
• The combination of Sono@NAT10 and anti-PD-1 therapy shows significant therapeutic potential for colorectal cancer.