IFN-γ drives long-term bone marrow niche dysfunction following doxorubicin-based chemotherapy.

Cancer survivors experience long-term skeletal and hematopoietic complications that limit quality of life following chemotherapy (CTX), yet the mechanisms underlying these defects remain incompletely understood. In this study, we used a murine model of doxorubicin (DOX)-based leukemia induction therapy to show that CTX induces inflammatory remodeling of the bone marrow (BM) niche. DOX treatment resulted in a loss of arteriolar vasculature, blockade of mesenchymal stromal cell (MSC) differentiation, trabecular bone loss, and reduced niche capacity to maintain hematopoietic stem cells. These defects were accompanied by aberrant immune activation within the BM, marked by increased interferon gamma (IFN-γ) production by CD8+ T cells. Inhibition of IFN-γ signaling partially restored arteriolar vessels and adipogenic differentiation. Furthermore, combined IFN-γ blockade with deferoxamine mesylate, which promotes vascular recovery, attenuated CTX-associated skeletal damage. Consistent with these findings, paired BM samples collected at diagnosis and after CTX from patients with leukemia exhibited altered MSC lineage priming, upregulation of inflammatory pathways, and expansion of BM CD8+ memory T cells after treatment. Together, these findings implicate IFN-γ-driven chronic inflammatory remodeling as a central mechanism of CTX-associated BM niche dysfunction and pinpoint inflammatory signaling as a potential target to preserve BM function and long-term tissue integrity.