The link between macrophage polarization and response to radiotherapy in cancers: mechanisms and therapeutic opportunities.

Macrophages, as central players in the tumor microenvironment (TME), exhibit remarkable plasticity, shifting between pro-inflammatory M1 and immunosuppressive M2 states. This polarization directly influences the response to radiotherapy in cancers. While M1 macrophages promote antitumor immunity, M2 macrophages contribute to immune evasion, metastasis, and treatment resistance. Ionizing radiation, while designed to kill tumor cells, can inadvertently alter macrophage polarization within the TME. High-dose and particle-based radiotherapies tend to favor M1 polarization, enhancing tumor control, while conventional radiotherapy often induces M2 macrophages, promoting radioresistance. These shifts in macrophage phenotype are driven by changes in metabolic signaling, hypoxia, and cytokine production within the TME, which together dictate the outcome of therapy. Emerging strategies aim to manipulate macrophage polarization to overcome radiotherapy-induced resistance, including the use of immune checkpoint inhibitors, nanoparticles, and metabolic reprogramming agents. By targeting macrophage recruitment, survival, and reprogramming, these therapies can potentially improve the efficacy of radiotherapy and reduce tumor recurrence. Understanding and leveraging macrophage plasticity holds promise for optimizing cancer treatment and enhancing patient outcomes in the era of precision oncology.