Functional reprogramming of bone marrow neutrophils in tumor-driven emergency granulopoiesis

Chronic inflammation is a defining feature of tumor progression, with neutrophils serving as key mediators linking cancer to systemic immune dysregulation. While their pro-tumoral functions in circulation and tumor sites are well established, how tumor progression influences neutrophil biology within the bone marrow remains poorly understood. We hypothesized that tumor progression is associated with emergency granulopoiesis, alterations in the G-CSF/G-CSFR axis, and functional changes in bone marrow neutrophils. This study aimed to investigate how tumor progression reconfigures granulopoiesis and neutrophil function within the bone marrow during systemic immune remodelling.

Using Dalton's lymphoma murine model, we examined the dynamics of bone marrow neutrophils at various stages of tumor progression. Neutrophil frequency, receptor expression, and effector functions were measured through flow cytometry, immunocytochemistry, NETosis, and phagocytosis assays.

Tumor-bearing mice displayed a marked expansion of BM Ly6G⁺ neutrophils, concomitant with elevated G-CSF levels and increased G-CSFR expression, confirming the induction of emergency granulopoiesis. These changes were paralleled by altered retention and egress signals, with upregulated CXCR2 and downregulated CXCR4, indicating accelerated mobilization of neutrophils and disrupted homeostasis of the bone marrow microenvironment. Functional profiling revealed a profound shift in the BM neutrophil phenotype: enhanced granule proteins such as NE, MPO, MMP-9, and cathepsin G, increased ROS generation, heightened NETosis, and augmented phagocytosis.

Together, these data demonstrate that tumor progression is associated not only with systemic neutrophil expansion but also with marked alterations in neutrophil abundance, activation status, and effector functions within the bone marrow. These findings suggest that tumor-associated immune remodulation may originate, at least in part, within the hematopoietic niche and precede the accumulation of activated neutrophils in peripheral tissues. Furthermore, the concomitant alterations in G-CSF/G-CSFR signaling and the CXCR2/CXCR4 axis highlight potential mechanisms underlying neutrophil remodeling during tumor progression. Collectively, our findings identify the bone marrow as an important site of tumor-associated neutrophil reprogramming and provide a rationale for exploring neutrophil-associated signaling pathways as therapeutic targets in cancer-associated systemic inflammation.