Macrophages promote tumor growth by phagocytosis-mediated cytokine amplification in Drosophila

Macrophages in the tumor microenvironment have been suggested to play a key role in driving tumor progression, but the underlying mechanism remains unclear. Here, we show in Drosophila imaginal discs that the phagocytic activity of mature phagocytic plasmatocytes, a subtype of Drosophila macrophages, promotes the growth of malignant tumors composed of epithelial cells that express activated Ras in combination with a scribble (scrib) mutation, which impairs cell polarity (RasV12/scrib). Mechanistically, caspase activation in dying RasV12/scrib cells induces infiltration of mature phagocytic plasmatocytes into RasV12/scrib tumors via reactive oxygen species (ROS) production, forming a feedback loop that reinforces caspase activation. Once inside the tumors, these plasmatocytes phagocytose caspase-activated RasV12/scrib cells exhibiting phosphatidylserine (PS) on their surface, which in turn induces unpaired 3 (Upd3, a homolog of interleukin-6 [IL-6]) production by the mature phagocytic plasmatocytes through the Draper-mediated engulfment pathway. This triggers non-autonomous induction of upds gene expression in RasV12/scrib tumors, leading to JAK/STAT-mediated boosting of tumor growth. Our findings uncover a mechanism of non-autonomous tumor progression by the phagocytic activity of macrophages, reminiscent of the cytokine amplification mechanism observed in the mammalian immune response.