Inflammatory reprogramming of monocytes disrupts tumor dormancy and promotes distant tumor spread

Dormant tumor cells represent a significant obstacle to durable cancer remission, as they can remain clinically silent for years and later give rise to recurrence and metastasis. While chronic inflammation is increasingly recognized as a trigger for dormancy escape, the cellular drivers and molecular pathways that awaken dormant tumors remain insufficiently understood. We used a tamoxifen-induced ROSA26.vFLIP; Csf1rCreERT2 mouse model to specifically activate NF-κB pathway-mediated inflammation in monocyte lineages. By combining this model with dormant pancreatic and breast cancer models, we were able to investigate the role of inflammatory monocytes in the awakening of dormant tumors and cancer metastasis. We used single-cell RNA sequencing to depict the immune landscape in the tumor microenvironment. Furthermore, we isolated splenic Ly6C⁺ monocytes and performed bulk RNA sequencing to identify transcriptomic changes in inflammatory monocytes. In the pancreatic cancer model, once vFLIP was induced in Csf1r⁺ monocytes, previously dormant tumors under immune control began to regrow. In the breast cancer model, the situation differed, but the trend remained consistent: FLIP⁺ monocytes were associated with an increased burden of lung metastases. Consistent with oncological behavior, significant substantial change of host hematopoiesis was observed—an increase in the proportion of CD4⁺ T cells, a significant increase of neutrophils, and a shrinkage of CD8⁺ T cells, both local and systemic. Transcriptomic results provided molecular evidence for this phenotype: FLIP⁺ monocytes upregulated multiple inflammatory mediators (such as Il1⍺, Il6, and Il12⍺) and a series of NF-κB target genes. Conversely, when NF-κB p50 was knocked out while vFLIP was induced in the same lineage, CD8⁺ T cells were preserved, and tumor growth and metastasis were significantly inhibited. These observations suggest that vFLIP–NF-κB-driven monocyte inflammatory reprogramming is a key driver of dormant tumor reactivation and metastatic progression. By delineating p50-dependent pathways and key cytokine programs, our study provides a mechanistic framework for developing therapeutic strategies that aim to prevent dormancy escape and relapse in cancer.