Immunological and transcriptomic analysis of febrile neutropenia in hematological malignancies: SOCS3/IL-6/NETs axis and NOD-like receptor signaling dysregulation

Abstract Objective: Chemotherapy-related febrile neutropenia (FN) is a high-risk complication in patients with hematological malignancies (HM), significantly increasing the risk of mortality. This study aims to identify early predictive biomarkers for the occurrence, progression, and prognosis of FN by dynamically monitoring immunological characteristics and transcriptomic changes in HM patients following chemotherapy. Methods: A total of 140 HM patients who developed neutropenia after chemotherapy were enrolled. Lymphocyte subsets were detected using flow cytometry, cytokines were measured via enzyme-linked immunosorbent assay (ELISA), and differentially expressed genes (DEGs) were identified through whole-transcriptome RNA sequencing combined with bioinformatics analysis. GO/KEGG enrichment analysis was further conducted to elucidate key pathways. Results: IL-10 levels were reduced before infection in FN patients, and IL-6 levels increased during grade 5 infection. IL-6 levels increased during the acute phase and decreased during the recovery phase. Compared with the non-fever group, 1,077 DEGs were identified in the fever with neutropenia group, with up-regulated genes primarily enriched in the extracellular domain and Staphylococcus aureus infection pathways. Compared with the grade 3 infection group, the grade 4 infection group identified 2,169 DEGs, significantly enriched in the neutrophil extracellular trap (NET) formation pathway, which may be associated with low SOCS3 expression and elevated IL-6 promoting NET formation. Compared with the survival group, the death group identified 2,286 DEGs, with downregulated genes primarily enriched in the extracellular domain and NOD-like receptor signaling pathway, and reduced IL-10 levels associated with sustained activation of this pathway. Conclusion: Dysregulation of the SOCS3/IL-6/NETs axis is a key mechanism in the progression of FN. Abnormal NOD-like receptor signaling pathways and reduced IL-10 levels may affect patient prognosis. The results of this study provide candidate biomarkers for the early identification of high-risk patients and the development of personalized treatment plans. Keywords: Malignant hematological diseases; febrile neutropenia; whole-transcriptome RNA sequencing; cytokines; biomarkers