Tumor‐Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation

Tumor-associated macrophages (TAMs) represent the most abundant immune cell population within the tumor microenvironment and are central drivers of malignant progression and treatment resistance. High TAMs infiltration in solid tumors consistently correlates with poor clinical outcomes, largely due to their role in establishing an immunosuppressive milieu that supports tumor growth, metastasis, and undermines the efficacy of chemotherapy, radiotherapy (RT), and immune checkpoint inhibitors. Although TAMs are well-recognized promoters of tumor progression, the development of effective strategies to therapeutically target them remains an unmet clinical need. In this review, we examine the multifaceted mechanisms through which TAMs contribute to malignancy, including phagocytic signaling modulation, metabolic reprogramming, exosomal communication, and crosstalk with other immune cells. We also evaluate three key therapeutic strategies: blocking TAMs recruitment and survival, reprogramming TAMs toward antitumor phenotypes, and the emerging approach of chimeric antigen receptor macrophage therapy. Furthermore, we highlight the synergistic potential of integrating TAMs-targeted strategies with conventional chemotherapy, RT, and immunotherapeutic approaches. By synthesizing current clinical evidence, this review aims to inform the rational design of next-generation TAMs-targeted interventions and to propose novel strategies for overcoming treatment resistance.