SLC7A7 Downregulation in Monocytes Drives Immunosuppression and Osteosarcoma Progression

Metabolic reprogramming and the formation of an immunosuppressive tumor microenvironment(TME) are hallmarks of osteosarcoma (OS). However, the metabolic characteristics of OS and its associated immune microenvironment remain largely unknown.

The single-cell data were processed for dimensionality reduction and cell-type annotation by using the Seurat package. Pseudotime analysis and metabolic difference prediction were performed using the SCPA algorithm to predict the metabolic profiles of immune cells. Through integrative analyses using BeyondCell and scMetabolism, three distinct cancer cell subpopulations were identified. Metabolic flux potential and intercellular metabolic communication within each subpopulation were subsequently quantified using METAFlux and Mebocost. Spatial colocalization analysis and intercellular communication prediction were conducted using SpaCET and CellChat. Furthermore, qRT-PCR and survival analyses were performed on our cohort of OS patients.

Monocytes emerged as the predominant immune cell population within OS tissues, displaying pronounced metabolic reprogramming marked by significant upregulation of glycolysis and tryptophan metabolism. Additionally, three cancer cell subpopulations with distinct chemosensitivity profiles were identified; Subpopulation 2, characterized by high expression of CCNA2, UBE2C, and CENPF, demonstrated significantly reduced sensitivity to methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide. Moreover, both cancer cells and monocytes function as key metabolic regulators, with glutamine serving as a critical metabolic mediator. Monocytes were predominantly localized in proximity to tumor cells and exhibited activation of signaling pathways such as SPP1 and ICAM. SLC7A7 expression was significantly downregulated in OS tissues, and its expression level was correlated with patient prognosis. Furthermore, monocytes exhibiting SLC7A7 downregulation may display aberrant recruitment patterns and functional deficits, potentially playing a pivotal role in supplying glutamine to OS cells and fostering an immunosuppressive TME.

This study provides a preliminary characterization of the metabolic landscape of OS and its associated immune microenvironment. Targeting SLC7A7-deficient monocytes may represent promising strategies for enhancing the efficacy of immunotherapy in OS.