Targeted Reprogramming of TREM2-Positive Macrophages and MRI-Guided Immune Monitoring in Colorectal Cancer Using...

Area of Science:

• Oncology
• Immunology
• Nanomedicine

Background:

• Colorectal cancer (CRC) exhibits an immunosuppressive tumor microenvironment (TME) that hinders effective treatment.
• Triggering receptors expressed on myeloid cells 2 (TREM2)-positive tumor-associated macrophages (TAMs) contribute to immune evasion and therapy resistance in CRC.

Purpose of the Study:

• To develop and evaluate a theranostic nanoplatform (CSF1R-IN-3@Mn@MPDA-antiTREM2, CMMT) for reprogramming TAMs and enabling magnetic resonance imaging (MRI)-guided immune monitoring in CRC.
• To investigate CMMT's ability to overcome immunotherapy resistance by modulating the TME.

Main Methods:

• CMMT, a manganese-doped mesoporous polydopamine nanoplatform with anti-TREM2 antibodies, was designed for pH-responsive drug release and selective targeting of TREM2+ M2 macrophages.
• The study assessed CMMT's efficacy in reprogramming M2-TAMs to M1 phenotypes and its synergistic effect with anti-PD-L1 therapy in orthotopic CRC models.
• CMMT's performance as an MRI contrast agent for monitoring TME remodeling was evaluated.

Main Results:

• CMMT demonstrated pH-responsive release of CSF1R inhibitor CSF1R-IN-3 and selectively targeted TREM2+ M2 macrophages (4.2-fold higher uptake than M1).
• CMMT synergized with anti-PD-L1 therapy, significantly reducing tumor volume (72.5% vs. 42.1% for monotherapy) and extending median survival (28 to 52 days) in CRC models.
• CMMT served as an effective MRI contrast agent, with T1 signal intensity correlating with intratumoral TREM2+ macrophage density (r = -0.71, P < 0.05).

Conclusions:

• The CMMT theranostic platform effectively reprograms TAMs and enhances anti-PD-L1 immunotherapy in CRC models.
• CMMT facilitates non-invasive monitoring of TME remodeling via MRI, offering a promising strategy to overcome immunotherapy resistance in colorectal cancer.