Molecular PET imaging of tumor-associated macrophages in precision oncology

Tumor-associated macrophages (TAMs) represent a dominant, plastic component of the tumor microenvironment (TME) that orchestrates immunosuppression, angiogenesis, and therapeutic resistance. Since static biopsies fail to capture the spatiotemporal heterogeneity and dynamic phenotypic evolution of TAMs (e.g., M1/M2 polarization), non-invasive imaging is critical. This review systematically critiques the evolution of Positron Emission Tomography (PET) strategies for TAM quantification, classifying innovations into metabolic, functional, and molecular approaches. Moving beyond the limitations of indirect methods-such as [¹⁸F]FDG and "Trojan horse" nanoparticles constrained by mononuclear phagocyte system (MPS) sequestration-we emphasize the paradigm shift toward high-affinity molecular probes. These target specific biomarkers (e.g., CD206, CD163, CSF1R) and recruitment pathways (e.g., CCR2). We particularly highlight the clinical potential of nanobody- and peptide-based tracers, which demonstrate superior tumor penetration and rapid clearance compared to full-sized antibodies. Concluding with an analysis of translational hurdles, such as interspecies marker discordance, we propose future directions that integrate theranostics, spatial transcriptomics, and AI-driven radiomics. Ultimately, molecular TAM-PET imaging is poised to evolve from an experimental tool into a precision oncology platform for patient stratification and monitoring of immunomodulatory therapies.