In a groundbreaking study from Nagoya University, scientists have uncovered a paradoxical mechanism by which the immune system, instead of suppressing tumors, can inadvertently accelerate their growth. The research, conducted using genetically engineered fruit flies as a model organism, reveals that macrophages—the immune cells typically known for defending the body by engulfing harmful entities—may actually fuel cancer progression when they consume dying cancer cells. This discovery challenges conventional understanding and offers a fresh perspective on the complex interplay between immune cells and tumors.
Typically, macrophages perform phagocytosis, a process by which they engulf and digest dying or dead cells, aiding in tissue cleanup and repair. However, the Nagoya University team showed that when macrophages engulf dying cancer cells within tumors, they begin producing inflammatory signaling molecules called cytokines. These cytokines initiate a cascade of molecular events inside the surviving cancer cells, leading to sustained tumor growth and proliferation. This unexpected finding underscores the intricate ways cancer cells can hijack normal biological processes for their advantage.
The key molecular actors identified in this study are the JAK and STAT proteins, which play central roles in cell signaling pathways governing growth, immune responses, and tissue maintenance. Upon activation by macrophage-derived cytokines, JAK and STAT proteins stimulate surviving cancer cells to produce their own cytokine molecule called Upd3, an analog of human interleukin-6 (IL-6). Through this self-reinforcing feedback loop, cancer cells amplify growth-promoting signals, creating a microenvironment conducive to tumor expansion and resistance to conventional immune attacks.
Fruit flies offer a powerful model system for dissecting these interactions due to their conserved immune and genetic pathways with humans. The researchers generated minute tumors in the fly’s eye tissue and applied fluorescent markers to live-track the behavior of cancer cells and macrophages using high-resolution microscopy. By selectively switching genes on or off within the flies, the scientists were able to manipulate the macrophages’ phagocytic activity and cytokine production, precisely elucidating the chain of events that drive tumor growth.
One striking outcome of this investigation was the demonstration that interrupting any stage of this feedback loop—with either genetic modifications that hinder macrophage engulfment of dying cancer cells or by suppressing cytokine production—resulted in a significant reduction of tumor expansion. These findings carry profound implications for cancer therapy, particularly interventions that traditionally seek to enhance immune cell activity to eliminate tumors. Augmenting macrophage phagocytosis without understanding this feedback mechanism could potentially exacerbate tumor growth instead of impeding it.
Moreover, the study highlights the cunning adaptability of cancer cells, which are not mere recipients of external growth signals but active participants in amplifying their own survival and proliferation cues. By co-opting the JAK-STAT signaling pathway and producing Upd3 cytokines themselves, cancer cells create a self-sustaining loop that exaggerates inflammatory signals within the tumor microenvironment. This insight clarifies why certain aggressive cancers with high rates of cell death paradoxically continue to grow despite immune infiltration.
Senior researcher Professor Shizue Ohsawa emphasized the evolutionary conservation underpinning these phenomena, noting that the molecular pathways identified in fruit flies share significant similarities with those in humans. This conservation raises the possibility that similar macrophage-cancer cell interactions may underlie tumor progression in human cancers, especially in cases where cell death within tumors is prevalent. Understanding these mechanisms could unveil new therapeutic targets aimed at disrupting the pathological dialogue between macrophages and cancer cells.
From a broader perspective, this research may reshape strategies in immunotherapy, encouraging a more nuanced approach that considers not only the activation but also the behavioral consequences of immune cells within the tumor microenvironment. Blocking the deleterious aspects of macrophage phagocytosis or cytokine amplification may prove vital in tempering tumor-promoting inflammation. This approach diverges from the current paradigm of broadly boosting immune system activity and highlights the need for precision in mobilizing immune defenses against cancer.
The integration of advanced genetic tools, live-cell imaging, and molecular analyses enabled the researchers to unravel these complex dynamics with remarkable detail. The study’s elegant design also underscores the relevance of invertebrate models for uncovering fundamental principles of human disease. By illuminating the molecular crosstalk between dying cancer cells, immune phagocytes, and surviving tumor cells, the work opens avenues for the development of drugs that specifically target the cytokine feedback network to inhibit tumor growth.
Published in the journal Current Biology, this study not only challenges existing assumptions about immune cell roles in cancer but also encourages a reevaluation of therapeutic strategies that harness or modulate the immune system. The identification of Upd3 as a key cytokine in this process spotlights IL-6-related signaling pathways as promising candidates for targeted therapies in oncology. Future research may expand on these findings to explore the translational potential in human cancers.
This discovery also exemplifies the complex duality of immune responses within cancer: while immune cells can attack tumors, under certain conditions, they may inadvertently create a microenvironment that supports tumor survival and expansion. Therapeutically, this underscores the importance of discerning context-dependent immune cell functions to avoid unintended consequences in cancer treatment. As the field of immuno-oncology advances, the detailed molecular understanding provided by this research will inform the design of safer, more effective interventions.
In conclusion, the Nagoya University study revolutionizes our conception of macrophage function in cancer biology. The revelation that macrophage phagocytosis of dying cancer cells can induce a growth-promoting feedback loop mediated by cytokine signaling challenges the conventional wisdom guiding cancer immunotherapy. This novel insight lays critical groundwork for developing next-generation treatments that finely tune immune system activities to suppress rather than promote tumor growth, marking a significant stride toward conquering cancer.
Subject of Research: Animals
Article Title: Macrophages promote tumor growth by phagocytosis-mediated cytokine amplification in Drosophila
News Publication Date: 25-Jun-2025
Web References: http://dx.doi.org/10.1016/j.cub.2025.05.068
References: Hirooka et al., 2025, Current Biology, DOI: 10.1016/j.cub.2025.05.068
Image Credits: Eri Hirooka, Nagoya University
Keywords: Tumor microenvironments, Macrophages, Phagocytosis, Cytokines, Tumor growth, Cancer cells, Immune cells
