Targeting MDSCs in Cancer: Emerging Immunotherapeutic and Metabolic Strategies

Shubhankar Dash¹Patryk Firmanty¹Monika Chomczyk¹Vakul Mohanty²Wenxue Ma³Natalia Baran^4*

• ¹Instytut Hematologii i Transfuzjologii, Warsaw, Poland
• ²MD Anderson Cancer Center Department of Bioinformatics and Computational Biology, Houston, United States
• ³Sanford Stem Cell Institute, Department of Medicine and Moores Cancer Center, University of California San Diego, San Diego, United States
• ⁴Universitaetsklinik fuer Hematologie und hematologisches Zentral Labor, InselSpital Bern, Bern, Switzerland

Myeloid-derived suppressor cells (MDSCs) are a diverse group of immature myeloid cells critically involved in establishing an immunosuppressive environment within tumors. They impede effective anti-tumor immune responses through multiple mechanisms, including metabolic reprogramming, cytokine secretion, and immune checkpoint ligand expression. This immunosuppressive activity enables tumor progression and resistance to therapies, including immunotherapy. Recent advances reveal that targeting the metabolic pathways of MDSCs can impair their suppressive functions, offering promising strategies to enhance anti-cancer immunity. Approaches such as metabolic inhibition, direct depletion, blockade of recruitment and expansion, and promotion of differentiation into mature immune cells are under active investigation. Combining these strategies with immune checkpoint inhibitors and cell-based therapies, such as cancer vaccines and adoptive T-cell or NK-cell therapies, holds significant potential for overcoming immune resistance. Nonetheless, challenges including MDSC heterogeneity, toxicity, and biomarker validation must be addressed to optimize clinical translation. This review comprehensively covers current insights into the immune-metabolic mechanisms underpinning MDSC-mediated immunosuppression in the tumor microenvironment. It explores emerging therapeutic strategies aimed at targeting MDSCs through metabolic interventions, depletion, and modulation of their recruitment and differentiation. Furthermore, it discusses the integration of MDSC-targeted approaches with existing immunotherapies, highlights ongoing clinical trials, and assesses future directions, such as personalized, biomarker-driven treatments. Ultimately, this review underscores the potential of MDSC-focused therapies to significantly improve the efficacy of cancer immunotherapy and overcome mechanisms of tumor immune evasion.