Macrophages are immune cells with a natural ability to enter solid tumors. They can engulf cancer cells, present tumor signals to other immune cells, and help coordinate anti-tumor responses, making them promising candidates for cell-based cancer therapy. However, tumors often weaken the immune cells that enter them. Solid tumors are commonly acidic and filled with signals that suppress immune activity. Under these conditions, macrophages can lose their cancer-fighting function and may even begin to support tumor growth, which has limited the effect of macrophage-based adoptive cell therapy.
A research team has developed a new strategy to help macrophages stay active inside tumors. The team attached tiny zinc aluminum layered double hydroxide patches to the surface of primary macrophages. These patches are linked to the cell surface through CD11b, a marker found on macrophages. The engineered macrophages are designed to remain stable under normal body conditions and become activated after they reach acidic tumor tissue.
The patches work in two ways. When the engineered macrophages enter acidic tumor tissue, the patches break down and release zinc ions, which work together with DNA released by tumor cells to activate the STING pathway, an important immune signaling pathway that helps switch macrophages toward a cancer-fighting state. At the same time, the patches reduce tumor acidity by consuming excess protons, changing the local tumor environment that normally suppresses immune function. By combining immune-cell reprogramming with tumor-environment remodeling, the strategy helps macrophages regain anti-tumor activity where it is most needed.
Guided by single-cell sequencing analysis of breast cancer samples, the therapeutic design was developed based on key observations: numerous tumor-associated macrophages exhibited a tumor-promoting phenotype, alongside a functional shift from anti-tumor macrophages to pro-tumor counterparts. Based on these discoveries, the research team engineered a therapy capable of reversing this macrophage polarization imbalance within the tumor microenvironment. In preclinical breast and pancreatic tumor models, patch-modified macrophages markedly suppressed tumor progression and metastasis formation. Beyond immediate anti-tumor effects, the treatment induced sustained anti-tumor immune memory, indicating its potential to block tumor recurrence, while no measurable systemic toxic side effects were observed in the study.
The study combines single-cell analysis with a simple surface-engineering method. Instead of permanently changing macrophages or activating the immune system throughout the body, the patch system uses tumor acidity as a local trigger. This design may help improve the precision and safety of macrophage-based cell therapy for solid tumors, providing a new way to engineer immune cells that respond to the tumor microenvironment and highlighting the potential of using local tumor signals to guide more precise cancer immunotherapy.
Science Bulletin
Experimental study