Csf2rb-Dependent Development of Yolk Sac-Derived Macrophages Drives Persistent Pro-Tumorigenic Activity

Tissue-resident macrophages (RTMs), predominantly originating from embryonic progenitors, play a pivotal role in maintaining tissue homeostasis and immune regulation. Their functional diversity is shaped by both their developmental origins—including the yolk sac, fetal liver, and bone marrow—and the local tissue microenvironment. In this study, we identified a unique subset of RTMs in Lyz2cre-RosaYFP reporter mice that lack Lyz2 expression and persist long-term in peripheral tissues. These Lyz2-YFP- RTMs follow a distinct developmental trajectory, transitioning from Lyz2-YFP-CD117+CD45-AA4.1- early erythro-myeloid progenitors (EMPs) to Lyz2-YFP-CD117+CD45+AA4.1- intermediate EMPs in a Csf2rb-dependent manner. Transcriptional profiling reveals that yolk sac-derived Kupffer cells (KCs) lacking Lyz2 expression are enriched in genes associated with T cell chemotaxis and tumor immunity. Functionally, these Lyz2-never expressed (Lyz2-YFP-) KCs are preferentially localized within intratumoral regions, where they promote hepatocellular carcinoma progression by recruiting CD4+CD25+Foxp3+ regulatory T cells (Tregs) and inducing T cell exhaustion. Conversely, Lyz2-ever expressed (Lyz2-YFP+) KCs exhibit anti-tumor activity by enhancing effector CD8+ T cell function. Our findings unveil a long-lived subset of RTMs with sustained pro-tumorigenic potential, underscoring the critical role of their yolk sac-derived developmental trajectory in shaping their functional properties. This study provides novel insights into the ontogeny-dependent heterogeneity of RTMs and their dual roles in tumor immunity.