MDSCs as the Myeloid Checkpoint: Rethinking Cancer Immunotherapy Through Targeted Modulation

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a key role in cancer progression by promoting immune evasion, enabling tumor cells to escape immune destruction, and establishing an immunosuppressed tumor microenvironment (TME). They inhibit anti-tumor immunity through several methods, such as blocking T-cell activation, altering dendritic cell function, and interacting with other populations of immune regulatory cells. A growing body of evidence shows that MDSCs contribute to tumor expansion, metastasis, and resistance to immunotherapy at a significant rate. MDSCs are located at the center of immune suppression in the TME, prompting researchers to target MDSCs in the hope of developing effective therapeutic agents. Researchers are actively investigating strategies to deplete, block, or prevent the recruitment of MDSCs within the TME to restore immune function within the TME. Several types of therapies, including but not limited to small molecules, monoclonal antibodies, and combination therapies, are being evaluated, with a focus on the use of immune checkpoint inhibitors in conjunction with the aforementioned therapies. Early studies have shown promising results; however, significant challenges remain, including MDSC plasticity, tumor adaptation, off-target effects, and safety concerns. The objective of this review is to provide a complete overview of the biology, function, and clinical implications of MDSCs in cancer. In addition, an analysis of current and future therapies targeting MDSCs is presented, focusing on the importance of MDSC heterogeneity in advancing personalized immunotherapies and improving patient outcomes.