Biological sciences
June 25, 2025
Immune cells promoting tumor growth? How dying cancer cells turn their enemies into allies
An inflammatory feedback loop helps cancer hijack immune responses to spread tumors.
Scientists at Nagoya University in Japan studied what happens when macrophages—a type of immune cell—encounter dying cancer cells in tumors and discovered a mechanism that accelerates tumor growth. When cancer cells begin to die within tumors, they expose signals on their surface that indicate they are dying. Macrophages then detect these signals and engage in phagocytosis, where they eat dying cancer cells. Using fruit flies as a model organism, the scientists found this triggers production of proteins called cytokines, which activate growth signals in remaining cancer cells. These cells then produce more cytokines, causing an unexpected chain reaction that promotes tumor growth.
The study showed that blocking any part of this pathway, whether preventing the macrophages from eating dying cancer cells or stopping cytokine production, significantly reduced tumor growth. (Watch a macrophage eating a cancer cell here. Credit: Hirooka et al., 2025)
Good cells gone bad
When macrophages in fruit flies consume dying cancer cells, they produce an inflammatory cytokine called Upd3, a protein similar to human IL-6. This Upd3 activates JAK and STAT proteins inside living cancer cells. These proteins normally coordinate immune responses and tissue repair, but cancer cells hijack this process: They turn on genes that make them produce their own Upd3, enhancing JAK and STAT activation and promoting tumor growth.
“We used genetically modified fruit flies to study cancer because their immune system is similar to ours, and they offer a powerful model system for research in the laboratory. We created tiny tumors in their eye tissue and used fluorescent markers to track cancer cells and macrophages in real-time under microscopes,” Eri Hirooka, a PhD student at the Graduate School of Science at Nagoya University and lead author, explained.
To understand how these cells interact, the researchers turned genes on and off, added or removed specific proteins, and measured the effects on tumor growth. They observed macrophages consuming dying cancer cells and measured the cytokine signals being produced during this process.
When they genetically decreased the macrophages’ ability to eat dying cancer cells or decreased Upd3 production, tumor growth was significantly reduced. The results challenge the assumption that enhancing immune cell phagocytosis is always beneficial in cancer treatment—many therapies aim to boost immune cell activity, but this research shows that could backfire.
When cancer cells die, macrophages consume them and produce inflammatory cytokines. This activates JAK and STAT proteins in living cancer cells, enabling them to produce their own Upd3 and creating a growth-promoting feedback loop in fruit flies. Credit: Eri Hirooka, Nagoya University
Macrophages (blue) accumulate around tumor tissue (green) in fruit flies. Both macrophages and cancer cells produce the inflammatory cytokine Upd3 (magenta). Dying cancer cells indicated by white arrowheads have just been consumed by macrophages. Credit Hirooka et al., 2025
Left image: Tumor cells (green) and dying cancer cells (magenta). Right image: Blocking macrophages from eating dying cancer cells suppresses tumor growth in fruit flies.
Credit: Hirooka et al., 2025
From flies to humans: Broader implications
The study shows that cancer cells are more cunning than expected. Instead of just receiving growth signals from immune cells, they actively boost those signals by producing their own Upd3. This mechanism may be universal across species because the dying cancer cells that start the whole process are commonly found in tumors, especially in advanced cancers.
Senior author Professor Shizue Ohsawa from Nagoya University’s Department of Biological Science noted that targeting this interaction between macrophages and dying cancer cells could be a new way to treat cancer in humans: “Because the molecular pathways between fruit flies and humans are evolutionarily preserved, understanding these mechanisms could explain why some cancers with high cell death rates can still grow aggressively and lead to improved treatments.”
The study, “Macrophages promote tumor growth by phagocytosis-mediated cytokine amplification in Drosophila,” was published in the journal Current Biology, on June 25, 2025, at DOI: 10.1016/j.cub.2025.05.068.
Authors:
Eri Hirooka, Ryo Hattori, Keisuke Ikawa, Tomoe Kobayashi, Makoto Matsuyama, Tatsushi Igaki, and Shizue Ohsawa
Top image:
When cancer cells die, macrophages consume them and produce inflammatory cytokines. This activates JAK and STAT proteins in living cancer cells, enabling them to produce their own Upd3 and creating a growth-promoting feedback loop in fruit flies. Credit Hirooka et al., 2025
Media Contact:
Merle Naidoo
International Communications Office, Nagoya University
Email: icomm_research@t.mail.nagoya-u.ac.jp
