Targeted Reprogramming of TREM2‐Positive Macrophages and MRI‐Guided Immune Monitoring in Colorectal Cancer Using CSF1R@Mn@MPDA‐Antitrem2 Nanoplatform

Abstract Colorectal cancer (CRC) poses a significant therapeutic challenge due to its immunosuppressive tumor microenvironmentl (TME). In this environment, triggering receptors expressed on myeloid cells 2 (TREM2+) tumor‐associated macrophages (TAMs) drive immune evasion and therapy resistance. In this study, CSF1R‐IN‐3@Mn@MPDA‐antiTREM2 (CMMT) is presented, a manganese‐doped mesoporous polydopamine nanoplatform conjugated with anti‐TREM2 antibodies, which integrates TAM reprogramming and magnetic resonance imaging (MRI)‐guided immune monitoring. CMMT has three key characteristics: 1) pH‐responsive release of the Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor CSF1R‐IN‐3 within acidic TME; 2) selective targeting of TREM2+ M2 macrophages, achieving 4.2‐fold higher uptake compared to M1 subsets ( P < 0.001); and 3) dual modulation of TREM2 and CSF1R pathways, polarizing M2‐TAMs toward pro‐inflammatory M1 phenotypes. In orthotopic CRC models, CMMT synergizes with anti‐PD‐L1 therapy, reducing tumor volume by 72.5% compared to 42.1% for monotherapy ( P < 0.001). It also extends median survival from 28 to 52 days. Importantly, CMMT acts as an MRI contrast agent, with T1 signal intensity correlating with intratumoral TREM2+ macrophage density (r‐ 0.71, P < 0.05), enabling non‐invasive assessment of TME remodeling. This theranostic platform bridges immune modulation and real‐time monitoring, providing a promising strategy to overcome immunotherapy resistance in CRC.