For the First Time, Scientists Filmed Immune Cells Devouring Live Cancer Cells
A camera caught something immunologists had long suspected but never seen: immune cells actively hunting and consuming live cancer cells in a living organism. The footage could change how we think about fighting melanoma.
A camera has done what decades of inference could not. Researchers at the Garvan Institute of Medical Research have filmed macrophages attacking and engulfing live melanoma cells in real time for the first time, capturing behavior that was theorized but never directly observed. The findings, published in the Journal of Experimental Medicine, add a new and unexpected player to the cancer immunity story, one that operates independently of the T cells and B cells that most immunotherapy strategies rely on.
CD169-Positive Macrophages Suppress Melanoma Tumor Growth
Macrophages are often called the immune system's housekeepers, cells that patrol tissues and consume debris, pathogens, and dying cells. They can make up as much as 30 percent of cells within a melanoma tumor, yet their precise role had remained contested. The field had largely come to view tumor-associated macrophages as a mixed bag, sometimes promoting tumor growth rather than restraining it.
The Garvan team identified a specific subgroup that bucks that reputation. CD169-positive macrophages, named for the CD169 protein they produce, congregate around the edges of melanoma tumors and continuously nibble away at live cancer cells. When the researchers selectively removed this subgroup in mouse models, melanoma tumors grew larger, confirming that these cells were actively suppressing tumor growth rather than passively coexisting with it. What made the result particularly striking, according to Professor Tri Phan, was that the attack appeared to occur independently of T cells and B cells, the immune players most commonly credited with fighting cancer, making the discovery unexpected and, in his words, genuinely exciting.
A New Target for Melanoma Immunotherapy
Melanoma is one of Australia's most common and deadliest cancers, and current immunotherapy approaches have a significant gap: immune checkpoint blockade, which works by unleashing T cells, fails to help roughly half of patients. Many of those patients have what researchers call "cold tumors," where T cells cannot penetrate the tumor environment at all. CD169-positive macrophages may offer a route around that wall.
Dr. Yuki Keith described the cells as biological informants: once they consume a cancer cell, they display a fragment of it on their surface like a red flag, a process that could recruit T cells into the tumor to finish the job. Targeting macrophage phagocytic activity through strategies like antibody-dependent cellular phagocytosis is already an active area of oncology research, and understanding how cancer cells evade phagocytic clearance, including through pathways like the CD47-SIRPa phagocytosis checkpoint axis, could help researchers design drugs that work alongside this newly documented macrophage behavior. The Garvan findings suggest that boosting the numbers of CD169-positive macrophages, making them more aggressive, or improving their ability to tag cancer cells could make immunotherapy work for a broader range of patients and potentially other cancer types beyond melanoma.
Intravital Two-Photon Microscopy Made the Discovery Possible
Seeing a macrophage eat a live cancer cell is not a petri-dish experiment. To capture the behavior in a living system, the team used intravital two-photon microscopy, an advanced imaging technique that allows researchers to observe cellular interactions inside living tissue in real time. Intravital microscopy of this kind provides real-time visualization of immune cell motility and cell interactions within the living tumor microenvironment, details that simply cannot be replicated in cell culture. The footage Dr. Keith obtained showed macrophages actively seeking out and engulfing live melanoma cells, not just clearing up debris after the fact.
To confirm the findings were relevant to human disease, the team also examined human tissue samples and found the same CD169-positive macrophages present in healthy skin and concentrated around the edges of melanoma tumors, mirroring what they had seen in the mouse models.
Open Questions About Macrophage-T Cell Coordination
The study is explicitly early-stage, and several critical questions remain unanswered. The most pressing is mechanistic: precisely how do CD169-positive macrophages interact with T cells after flagging cancer cell fragments? The "immune informant" hypothesis is compelling, but the signaling chain connecting macrophage consumption to T cell recruitment has not yet been mapped in this context. Research has also shown that tumor cell adhesion to neighboring cells can limit complete phagocytosis and promote partial nibbling instead, raising questions about how efficiently these macrophages can clear cancer cells in densely packed tumor tissue.
More broadly, the study reinforces that macrophage subtypes are context-dependent. The same broad cell type that is sometimes tumor-promoting in other cancers appears genuinely tumor-suppressing here. That complexity means any drug targeting this population will require precision, and developing those targeted drugs is identified as a necessary next step before any clinical application is possible.
What Comes Next for CD169 Macrophage Research
The Garvan team's immediate priorities are to map how CD169-positive macrophages communicate with T cells and to identify drug targets that could amplify their cancer-fighting behavior. Three potential intervention strategies are on the table: increasing the number of these macrophages within tumors, enhancing their appetite for cancer cells, or improving the efficiency with which they tag cancer fragments for T cell recognition.
The research was supported by Australia's National Health and Medical Research Council, the Australian Cancer Research Foundation, Cancer Institute New South Wales, and several philanthropic funders. If the macrophage-T cell communication pathway can be clarified and a viable drug developed to exploit it, the result could be a complementary approach to checkpoint blockade therapy that works for patients whose tumors are currently unreachable by T cells alone.
Evidence rating
INVESTIGATIONAL — 67/100
Preclinical mouse study with supporting human tissue histology. Demonstrates that CD169-positive macrophages suppress melanoma growth in vivo, but causal mechanism linking macrophage activity to downstream immune recruitment remains proposed rather than established. Primary findings have not yet been independently replicated, and no clinical efficacy data are available.
References
- Yuki Honda Keith, Emily Duchini, Xufeng Lin, et al. (2026). CSF1R-dependent CD169-positive macrophages locally constrain melanoma growth in the skin. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20252239
- Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy – Frontiers. frontiersin.org. https://www.frontiersin.org/articles/10.3389/fimmu.2021.751307/full
- Mingye Feng, Wen Jiang, Betty Y. S. Kim, Cheng Cheng Zhang, Yang-Xin Fu, Irving L. Weissman (2019). Phagocytosis checkpoints as new targets for cancer immunotherapy. Nature Reviews Cancer. https://doi.org/10.1038/s41568-019-0183-z
- Intravital Imaging of Immune Responses in the Cancer Microenvironment – PMC. NIH. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103756/
- Target cell adhesion limits macrophage phagocytosis and promotes trogocytosis – PMC. NIH. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150965/
