Polarization of Tumor Cells and Tumor‐Associated Macrophages: Molecular Mechanisms and Therapeutic Targets

Abstract Tumor‐associated macrophages (TAMs) are prominent constituents of solid tumors, and their prevalence is often associated with poor clinical outcomes. These highly adaptable immune cells undergo dynamic functional changes within the immunosuppressive tumor microenvironment (TME), engaging in reciprocal interactions with malignant cells. This bidirectional communication facilitates concurrent phenotypic transformation: tumor cells shift toward invasive mesenchymal states, whereas TAMs develop immunosuppressive, pro‐tumorigenic traits. Increasing evidence highlights metabolic reprogramming, characterized by dysregulation of lipid metabolism, amino acid utilization, and glycolytic activity, as the fundamental molecular basis orchestrating this pathological symbiosis. However, a comprehensive understanding of how metabolic reprogramming specifically coordinates the mutual polarization of tumor cells and TAMs is lacking. This review thoroughly examines the molecular mechanisms governing this co‐polarization process, detailing critical transcriptional regulators, essential signaling pathways, and the maintenance of adaptive phenotypes within the TME. Furthermore, this review critically assesses promising therapeutic strategies aimed at disrupting this alliance, including the use of metabolically targeted agents, engineered chimeric antigen receptor macrophages, and TAM‐selective nanoparticle delivery systems. These insights provide a crucial foundation for the development of next‐generation cancer immunotherapies focused on reprogramming pathological polarization dynamics to overcome treatment resistance and improve clinical outcomes.