MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy

Despite the success of cancer immunotherapy in treating hematologic malignancies, their efficacy in solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), which is mainly formed by myeloid-derived suppressor cells (MDSCs). MDSCs not only exert potent immunosuppressive effects that hinder the success of immune checkpoint inhibitors (ICIs) and adaptive cellular therapies, but they also promote tumor advancement through non-immunological pathways, including promoting angiogenesis, driving epithelial-mesenchymal transition (EMT), and contributing to the establishment of pre-metastatic environments. While targeting MDSCs alone or in combination with conventional therapies has shown limited success, emerging evidence suggests that MDSC checkpoint blockade in combination with other immunotherapies holds great promise in overcoming both immunological and non-immunological barriers. In this review, we discussed the dual roles of MDSCs, with a particular emphasis on their underexplored checkpoints blockade strategies. We discussed the rationale behind combination strategies, their potential advantages in overcoming MDSC-mediated immunosuppression, and the challenges associated with their development. Additionally, we highlight future research directions aimed at optimizing combination immunotherapies to enhance cancer therapeutic effectiveness, particularly in solid tumor therapies where MDSCs are highly prevalent.