Myeloid-derived suppressor cells in laryngeal squamous cell carcinoma: an underexplored immunosuppressive axis and strategic target for overcoming checkpoint inhibitor resistance

Abstract

Laryngeal squamous cell carcinoma (LSCC) shows a persistently low objective response rate to immune checkpoint inhibitors (ICIs) targeting the programmed death-1 (PD-1) pathway. Its immunosuppressive tumor microenvironment (TME), enriched in tumor-associated macrophages, immunosuppressive tumor-associated neutrophils (TANs), and regulatory T cells, is a principal driver of ICI failure. Yet one myeloid population central to ICI resistance across many malignancies has received no dedicated attention in this disease. Myeloid-derived suppressor cells (MDSCs) are heterogeneous, pathologically activated immature myeloid progenitors that suppress CD8+ T cell and natural killer cell cytotoxicity, promote regulatory T cell expansion, and sustain PD-1 blockade resistance through redundant mechanisms. In LSCC, tumor-derived G-CSF and GM-CSF activate the PI3K-AKT pathway in infiltrating neutrophils and upregulate PD-L1, and this same cytokine axis is an established upstream driver of MDSC differentiation and mobilization. The predominantly elderly, male, HPV-negative, tobacco-exposed patient profile further favors MDSC accumulation through aging-associated myeloid bias, senescence-associated secretory phenotype signaling, and chronic inflammation. Evidence support MDSCs as a clinically tractable immunosuppressive node in LSCC. These are the LSCC tumor secretome, the shared transcriptional landscape of polymorphonuclear MDSCs (PMN-MDSCs) and immunosuppressive TANs, and the clinical validation of circulating LOX-1+ PMN-MDSCs as predictors of ICI resistance in head and neck squamous cell carcinoma (HNSCC). Drawing on this evidence, we outline a mechanistic rationale connecting LSCC biology to MDSC expansion and argue that combining MDSC-targeting strategies with PD-1 blockade merits dedicated clinical investigation in this disease.