Functional Role of Granulocytic Myeloid-Derived Suppressor Cells in CAR-T Therapy: Insights from Single- Cell RNA Sequencing in Multiple Myeloma

Immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy, represent a pivotal approach in the treatment of multiple myeloma (MM). However, the complex immunosuppressive tumor microenvironment (TME) poses significant challenges to their efficacy. Among the immunosuppressive cells in the MM TME, granulocytic myeloid-derived suppressor cells (G-MDSCs) are predominant; however, their functions remain incompletely understood. In this study, a comprehensive analysis of G-MDSCs was conducted using single-cell transcriptomic data from seven MM patients before and post CAR-T therapy. The pathological activation and immunosuppressive roles of G-MDSCs were identified, and these features were found to be potentially linked to patient prognosis. Functional enrichment analysis revealed that G-MDSCs are key modulators of immune responses within the TME. GSEA analysis suggested that G-MDSCs regulate immune responses via the IFN-α/γ signaling pathway. Furthermore, G-MDSCs may facilitate immune evasion of MM cells by promoting cell proliferation through the IGF1-IGF1R axis and inhibiting T cells and other immune cells via the SIRPA-CD47 pathway. A risk prediction model based on differentially expressed genes in G-MDSCs demonstrated high prognostic accuracy (AUC = 0.94) and was validated by Kaplan-Meier survival analysis. Additionally, PTGS1 was identified as a key marker associated with high-risk groups, suggesting its potential as a therapeutic adjunct target to improve CAR-T treatment outcomes. Further in vitro experiments demonstrated that G-MDSCs may exert immunosuppressive functions through PTGS1 expression. This study provides new insights into the role of G-MDSCs in the MM TME and highlights potential therapeutic strategies to enhance CAR-T therapy efficacy.