Emergency Myelopoiesis Drives Immunosuppressive Monocyte Programming in Lymphoma

Lymphoma-associated secondary hemophagocytic lymphohistiocytosis (sHLH) is a highly fatal manifestation of cancer-induced immune dysregulation, yet how lymphoma reshapes myelopoiesis to generate pathogenic myeloid cells remains unclear. To define the malignant immune ecosystem, we performed single-cell RNA sequencing on paired bone marrow and peripheral blood samples from patients with B-cell lymphoma with sHLH (n=14) or without sHLH (n=7), with primary HLH carrying PRF1 or UNC13D mutations (n=6) included to distinguish cancer-driven remodeling from inherited immune defects (total 110,943 cells). Lymphoma-associated sHLH exhibited tumor-driven emergency myelopoiesis with expansion of myeloid-biased hematopoietic stem cells and granulocyte-monocyte progenitors (GMPs). These progenitors displayed activation of inflammatory pathways (TNF-α, IFN-γ) and were pre-imprinted with the MS1 immunosuppressive transcriptional program (S100A8/9, IL1R2, PLAC8, low HLA-DR), indicating that monocytic dysfunction originates at the progenitor stage within the tumor-altered bone marrow niche. MS1-like monocytes diverged into two terminal lineages; one lineage was preferentially expanded in sHLH and expressed pro-inflammatory cytokines (CXCL2, CXCL3, IL6), the regulatory cytokine IL10, and multiple immune checkpoint ligands (VSIG4, LILRB4). Cell-cell interaction and regulon analyses revealed an IL-6/IL-10-STAT3 signaling loop that reinforces MS1 programming and creates a self-sustaining immunosuppressive circuit. Functionally, the abundance of MS1-like monocytes inversely correlated with CD4+ and CD8+ T-cell frequencies, accompanied by loss of conventional dendritic cells, impaired antigen presentation, and metabolic hyperactivation of T cells with increased PD-1, TIM-3, and LAG-3 expression, suggestive of dysfunctional activation rather than classical exhaustion. These findings uncover a cancer-driven immunopathogenic mechanism in which lymphoma hijacks myelopoiesis to generate STAT3-dependent immunosuppressive monocytes that simultaneously amplify hyperinflammation and blunt anti-tumor immunity. Targeting emergency myelopoiesis or monocytic STAT3 signaling represents a therapeutic strategy for restoring immune competence in lymphoma-associated sHLH. Citation Format: Hyunsoo Cho, Jeong-Eun Kwak, June-Young Koh, Ja Min Byun, Youngil Koh, Junshik Hong, Dong-Yeop Shin, Inho Kim, Hee Young Ju. Emergency myelopoiesis drives immunosuppressive monocyte programming in lymphoma-associated secondary hemophagocytic lymphohistiocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1353.