JUN Specifies the Local Differentiation and Maintenance of Pro-tumoral Monocyte-Derived Macrophages

Abstract Tumor-associated macrophages (TAMs) play important roles in cancer progression and resistance to therapy. Recent studies have shown that TAMs include both long-lived resident tissue macrophages (RTMs) and short-lived monocyte-derived macrophages (MDMs) with limited proliferative potential. RTMs and MDMs have been suggested to play divergent roles in tumorigenesis; RTMs are aligned with trophic functions, whereas MDMs are enriched for immune-regulatory pathways. Here we established a specific role for the AP-1 factor JUN in the differentiation and maintenance of MDMs and the specification of pro-tumoral trophic functions during tumor development. Alternatively, the immune-regulatory functions of TAMs remained JUN-independent. JUN was required for the specification and maintenance of pro-tumoral TAMs that support blood vessel maturation and tumor growth. Single-cell transcriptomics analysis uncovered the alternative fates for tumor-infiltrating monocytes and the development of distinct TAM states associated with trophic functions and immune-regulation. These studies demonstrate an important role for JUN in the specification of pro-tumoral monocyte-derived TAMs that could offer opportunities for selective TAM-targeted therapies for cancer. Significance: JUN promotes the specification of pro-tumoral macrophages but is dispensable for pro-inflammatory macrophages, suggesting targeting the JUN pathway in myeloid cells could supress pro-tumoral macrophages while sparing anti-tumor inflammatory myeloid cells.