Myeloid-Derived Suppressor Cells and Radiotherapy: Regulation and Clinical Implications

Radiotherapy (RT) serves as a critical treatment modality for cancer, which not only destroys local tumor cells, but also exerts the "double-edged sword" impact on the immune system. While triggering anti-tumor immune response, RT also induces a great number of immunosuppressive cells, including a predominant cell population, myeloid-derived suppressor cells (MDSCs). Notably, the RT-induced MDSCs play a vital role in radioresistance. To enhance the efficacy of RT, numerous preclinical studies have elucidated the mechanisms by which RT modulates MDSCs, and evaluated the MDSC-targeted strategies to sensitize RT. Moreover, some clinical studies have explored drugs involved in MDSC-targeting to enhance the effectiveness of RT. However, though generally tolerable, the clinical benefits of combining these agents with RT are limited. Lacking specificity of MDSC-targeted agents is a major concern. Furthermore, several fundamental challenges complicate the investigation of MDSCs and their interplay with RT. These include the lack of specific biomarkers for MDSCs, their dynamic behavior during RT, differences between murine and human immune systems, the complexity of standard-of-care regimens, and the involvement of other immunosuppressive cell populations. Future investigations need to keep focusing on uncovering the features of MDSCs and their roles in RT, so that we can develop specific therapies to target MDSCs individually. This review covers the complicated regulatory network between RT and MDSCs, as well as current preclinical and clinical strategies targeting MDSC to sensitize RT, aiming to provide some insights and directions for cancer therapy.