Tumor-associated macrophages in cancer: from mechanisms to application

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Abstract
Tumor-associated macrophages (TAMs) are central constituents of the tumor microenvironment (TME), recruited from circulating monocytes through chemotactic signals, and they execute complex, multifaceted functions throughout tumor progression. Functionally heterogeneous, TAMs are broadly classified into distinct subtypes that display a dynamic duality, capable of shifting between tumor-suppressive and tumor-promoting states, though the pro-tumorigenic functions tend to dominate across multiple cancer types. The polarization of TAMs is modulated by diverse cytokines and signaling networks within the TME. Key pro-tumor mechanisms include activating proliferative signaling pathways, enhancing invasive and metastatic potential, establishing an immunosuppressive TME through immune cell interactions, and conferring therapy resistance. The spatial heterogeneity of TAMs further underscores the predictive relevance. Translational research increasingly focuses on TAM-targeting strategies such as inhibiting recruitment, depleting subsets, or reprogramming function. Emerging approaches, including nanomedicine-based targeting, macrophage-mediated therapies, and novel drug formulations, highlight the importance of combining conventional treatments with immune checkpoint inhibitors (ICIs). Such combinations help overcome therapeutic resistance and improve clinical outcomes. This review systematically summarizes recent advances in TAM biology and plasticity, biomarkers from single-cell and spatial analyses for distinguishing TAM subsets, and their prognostic relevance in immunotherapy. It also discusses TAM-targeting strategies and their synergistic potential with existing therapies. Together, these insights lay the foundation for next-generation cancer treatments that precisely target TAMs to overcome therapy resistance and improve patient survival.

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