Leukemia inhibitory factor (LIF) in acute graft-versus-host disease: A hypothesis-generating review

Leukemia inhibitory factor (LIF) is a multifunctional cytokine of the IL-6 family, originally identified in murine leukemia cells. Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), primarily affecting the intestine, liver, and skin. Preclinical studies suggest that LIF may protect against GvHD by preserving intestinal stem cells, reducing radiation- and cytokine-induced tissue injury, decreasing donor T-cell infiltration, and suppressing inflammatory cytokine production; importantly, it appears to preserve graft-versus-leukemia (GVL) activity. This review summarizes current knowledge on the immunopathogenesis of acute GvHD (aGvHD) and examines the emerging but limited evidence on the immunomodulatory role of LIF. We propose a hypothesis-driven framework for its potential therapeutic application. We highlight the immunomodulatory properties of LIF, including its roles in suppressing proinflammatory responses and promoting regulatory mechanisms. LIF's ability to reduce GvHD severity without compromising GVL highlights its potential as a therapeutic agent. Given the limited but promising data, further research is warranted to evaluate LIF's clinical applicability and safety in transplant recipients.