Macrophages are immune cells with a natural ability to enter solid tumours.

They can engulf cancer cells, present tumour signals to other immune cells, and help coordinate anti-tumour responses, making them promising candidates for cell-based cancer therapy.

However, tumours often weaken the immune cells that enter them. Solid tumours 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 tumour 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 tumours. The team attached tiny zinc aluminium 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 tumour tissue.

The patches work in two ways. When the engineered macrophages enter acidic tumour tissue, the patches break down and release zinc ions, which work together with DNA released by tumour cells to activate the STING pathway, an important immune signalling pathway that helps switch macrophages toward a cancer-fighting state.

At the same time, the patches reduce tumour acidity by consuming excess protons, changing the local tumour environment that normally suppresses immune function.

By combining immune-cell reprogramming with tumour-environment remodelling, the strategy helps macrophages regain anti-tumour 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 tumour-associated macrophages exhibited a tumour-promoting phenotype, alongside a functional shift from anti-tumour macrophages to pro-tumour counterparts.

Based on these discoveries, the research team engineered a therapy capable of reversing this macrophage polarisation imbalance within the tumour microenvironment.

In preclinical breast and pancreatic tumour models, patch-modified macrophages markedly suppressed tumour progression and metastasis formation.

Beyond immediate anti-tumour effects, the treatment induced sustained anti-tumour immune memory, indicating its potential to block tumour 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 tumour acidity as a local trigger.

This design may help improve the precision and safety of macrophage-based cell therapy for solid tumours, providing a new way to engineer immune cells that respond to the tumour microenvironment and highlighting the potential of using local tumour signals to guide more precise cancer immunotherapy.

Article: In situ macrophage reprogramming via micropatch engineering for safe and effective antitumor adoptive cell therapy

Source: Science China Press