Crosstalk of cancer stemness-neutrophils in outcome of intracranial germ cell tumors.

Background: Intracranial germ cell tumors (iGCTs) are categorized into germinomas (GEs) and non-germinomatous germ cell tumors (NGGCTs), which show divergent clinical outcomes with GEs having a significantly more favorable prognosis. This prognostic disparity suggests distinct biological characteristics, yet the association between tumor stemness and the host immune microenvironment, particularly in pre-treatment peripheral blood, remains poorly understood. Therefore, this study integrated multi-omics data, immune cell enrichment scores, and peripheral blood analyses to elucidate the relationship between cancer stemness indices and immune cells, especially neutrophils; and to evaluate its prognosis and treatment strategy in iGCTs. Methods: We included iGCT patients from Tiantan Hospital, all of whom underwent peripheral blood testing before pre-chemotherapy. In addition, gene expression microarray, 450K methylation data, and copy number variation data were obtained from the Gene Expression Omnibus (GEO) database. Bioinformatics analysis was used to assess and compare stemness, biological functions, immune microenvironment characteristics between GEs and NGGCTs. Furthermore, we specifically investigated the correlation between stemness indices and neutrophil levels in both subtypes. Results: Our analysis revealed that the stemness of GEs was significantly higher than that of NGGCTs. Functional enrichment analysis indicated that GEs are primarily involved in processes related to cell proliferation, whereas NGGCTs were mainly associated with extracellular matrix processes. Patients with GEs had better prognoses than those with NGGCTs, highlighting the crucial role of the tumor microenvironment on tumor progression. The immune landscape also differed substantially between the two subtypes, with distinct patterns of immune cell infiltration and response. Notably, the correlation between cancer stemness and neutrophil levels showed the most marked difference between GEs and NGGCTs. Our data further validated that neutrophil abundance is positively associated with increased malignancy in iGCTs, suggesting that neutrophils represent a key factor influencing iGCT outcomes. Conclusion: Our study demonstrates that the interaction between neutrophils and stemness contributes to the malignant progression of iGCTs, leading to adverse clinical outcomes. These findings not only advance our understanding of iGCT biology but also highlight potential novel therapeutic targets. Moreover, they provide a rationale for developing immunotherapy strategies aimed at modulating the neutrophil-stemness axis in iGCTs.