It is an established fact that more than half of cancer patients receive RT, which involves the use of ionizing radiation (IR) to target and destroy cancer cells. IR exerts its effect by inducing various forms of DNA damage, including single-strand and double-strand breaks, leading to the activation of different death mechanisms such as apoptosis, necrosis, and mitotic catastrophe. Despite the remarkable success of RT in cancer treatment, its efficacy is affected by several factors, among which TME is one of the important influences. The TME is defined as the complex ecosystem surrounding tumor cells, comprising immune cells, blood vessels, the extracellular matrix, and signaling molecules. Collectively, these elements influence tumor development and treatment response, providing an ecological niche that is essential for cancer [1]. An increasing number of studies have revealed that IR not only kills cancer cells directly, but also indirectly affects tumor growth and metastasis by altering immune cells (e.g., macrophages) and inflammatory mediators in the TME [2]. Furthermore, the combination of RT with a multitude of immunomodulators also enhanced tumor regression outside of the radiation field, also known as the abscopal effect [3], confirming that the biological effects of IR on TME components, especially immune effector cells, are key factors in the tumor's response to RT, but their underlying mechanisms remain to be further elucidated [4]. The resistance of tumor cells to radiation, the immunosuppressive state of the TME, and radiation damage to normal tissues are the main challenges of RT. Consequently, a focus in contemporary radiation oncology research is the optimization of therapeutic precision while maintaining treatment effectiveness through dose reduction.

Macrophages, as the important immune cells in TME, are involved in the occurrence and development of tumors, immune escape, and anti-tumor processes [5]. RT induces the recruitment of massive macrophages to the tumor site [6]. The polarization state and functional changes of macrophages in the TME and their dual roles during RT are crucial to the effect of RT [7,8]. On the one hand, M1 macrophages are capable of exerting anti-tumor effects by enhancing T-cell responses and promoting vascular normalization, thereby enhancing tumor radiosensitivity; on the other hand, M2 macrophages may reduce tumor radiosensitivity by secreting anti-inflammatory factors, promoting angiogenesis, and immune escape, and other mechanisms. For example, some studies have found that the number of M1 macrophages infiltrated is positively correlated with radiosensitivity [9]; On the contrary, the enrichment of M2 macrophages is often associated with radioresistance [10,11]. Therefore, the dual roles of macrophages in TME make them key regulators of RT efficacy. A deeper understanding of the dynamics between these two phenotypes could potentially unlock a new approach to RT, offering a breakthrough in the ongoing efforts to combat cancer.

Exosomes, as mediators of intercellular communication, are able to regulate the immune response and polarization status of macrophages in RT [12,13]. Chemokines affect the tumor response to RT by regulating the infiltration and polarization of macrophages. Therefore, the research will focus on the mechanism of action of macrophages in RT, the dynamic polarization changes of TAMs, and how to enhance tumor radiosensitivity by targeting TAMs. Interfering with macrophage function, especially by targeting the polarization state of macrophages, may become an important strategy to enhance the effectiveness of RT.

Although current research has made some progress on the mechanisms of the effects of RT on macrophage function, there are still many unsolved mysteries, especially how to precisely regulate macrophage function in different radiation types, doses of RT, and in different types of tumors. In addition, immunotherapy has shown great potential, which means that how to optimize the effect of RT through combined immunotherapy strategies, such as immune checkpoint inhibitors (ICIs), still requires further preclinical and clinical verification. Therefore, comprehensive research on the mechanisms of RT effects on TME, especially on TAMs, is of great theoretical and clinical significance. This review aims to systematically review the research progress on macrophages and tumor radiosensitivity and to prospect the future research direction, in order to provide new ideas for improving the efficacy of RT.