TAM-targeted nanomedicine in cancer: biological basis, therapeutic strategies, and translational perspectives

Tumor-associated macrophages (TAMs) are the most common immune cell type found in the tumor microenvironment. They are also key participants in the regulation of angiogenesis, metastasis, immune evasion, and therapeutic resistance. Recent single-cell transcriptomics and spatial profiling have shown that TAMs are extremely heterogeneous and functionally plastic beyond the traditional M1/M2 paradigm, and that more refined therapeutic strategies are required. Nanomedicine can integrate macrophage biology, the tumor microenvironment, and the engineering of the delivery system to design TAM-oriented interventions. With optimization of delivery systems (e.g. particle size, surface chemistry, ligands, therapeutic payloads, and the type of stimuli), multiple functionalities can be engineered to improve macrophage (in the tumor microenvironment) recruitment, depletion, reprogramming, and enhancement of TAM phagocytosis, antigen presentation, and immune regulation. Nanoparticles with biomimetic systems, macrophage membrane coating, as well as macrophage-derived extracellular vesicles and engineered exosome platforms, can also provide a wide array of options for TAM-oriented therapy. In this review, we provide an overview of the origin, heterogeneity, and functions of TAMs in cancer, and categorize TAM-targeted nanotherapeutics based on the principal approaches of recruitment blockade, tumor-promoting macrophage depletion, reprogramming, functional enhancement of phagocytosis and immune activation, and biomimetic drug delivery. We also present a comparison of representative nanoplatforms, highlight the latest clinical developments, and investigate key barriers to moving research from the lab to the clinic using nanomedicine, including delivery system design focused on targeting TAMs, safe and effective delivery to tumors, off-target effects on macrophages, ease of manufacture, and control of product quality. By combining TAM biology with the design of specialized nanocarriers and clinical research, this review outlines the main directions of research and provides a practical approach to the development of specialized TAM-targeted cancer nanomedicines.