Brain metastases have become an increasingly serious and urgent problem in cancer treatment. to 30 percent One patient with lung cancer, breast cancer, or melanoma develops brain metastases and treatment options are limited. prognosis is bad. Surgery is often risky, radiation provides only moderate control, and most drugs cannot cross the blood-brain barrier that protects the brain. The diagnosis of brain metastases remains a difficult turning point for patients and their families.

But a team at Wake Forest University School of Medicine may have found a new way to fight back. in research published in natural biomedical engineeringresearchers engineered macrophages to create a special anti-cancer drug called chimeric antigen receptor macrophages (CARMA). These cells are designed to hunt down cancer cells, cross the blood-brain barrier, and mobilize the rest of the immune system to join the fight.

“Treatment of brain metastases is incredibly difficult because most treatments simply cannot reach the brain.” Wu Shiying“This is an important finding,” said lead author and oncologist at Wake Forest University School of Medicine. press release. “But macrophages naturally know how to invade the brain. So we asked, ‘What if we gave macrophages the ability to recognize and destroy cancer cells once they got there?'”

Why macrophages?

Macrophages naturally infiltrate solid tumors, including areas of hypoxia and necrosis that are difficult for T cells to invade.

—Shih-Ying Wu, Wake Forest University School of Medicine

Compared to CAR-T therapy, macrophages uniquely suited Targeting the brain. Macrophages can move through dense tumor tissue, survive in hypoxic environments, and even digest damaged cells in the tumor center.

“Macrophages naturally infiltrate solid tumors, including areas of hypoxia and necrosis, which are difficult for T cells to penetrate,” said Shih-Ying Wu. DDN. “Once internalized, CARMA cells remain functional, phagocytosing tumor cells, remodeling the extracellular matrix, polarizing into a pro-inflammatory state, and presenting tumor antigens to activate endogenous immunity.”

In this study, the researchers genetically reprogrammed macrophages to express a CAR that recognizes mesothelin, a tumor-associated protein that is highly expressed in lung cancer cells that metastasize to the brain. To further enhance antitumor activity, the researchers fused this receptor to MyD88 (myeloid primary response 88), a signaling protein that enhances phagocytic activity and proinflammatory signaling. The result is cells with improved tumor recognition and enhanced immune activation.

In preclinical studies, CARMA has shown remarkable results. The engineered macrophages crossed the blood-brain barrier, invaded metastatic lesions, and directly attacked tumor cells. They also released the powerful signaling molecule TNF (tumor necrosis factor), inducing a “bystander” effect and harming nearby cancer cells that did not express the target antigen. Importantly, TNF levels were high enough to kill cancer cells, but remained below the threshold that could damage neurons, suggesting a promising safety profile.

Beyond direct cytotoxicity, CARMA appears to rewire the immune response in a way that is more durable than the engineered cells themselves. “In the relapse model without reinjection of CARMA, tumors remained controlled for one month, demonstrating a memory-like antitumor effect,” he said. Konosuke Watanabesenior author and oncologist at Wake Forest University School of Medicine. “In studies in humanized mice, CARMA enhanced antigen presentation pathways and enhanced T cell cytotoxicity in co-cultures. This shows that CARMA can activate and enhance adaptive immune responses even after the cells have left the tumor.”

A new class of cancer immunotherapy

The advantages of CARMA over conventional CAR-T cells are compelling. CAR-T therapy has revolutionized treatment blood cancerHowever, it has not yet been applied to brain tumors. limited It is caused by decreased osmotic ability, neurotoxicity, and delayed reaction time. CARMA has only been tested in preclinical studies, but in addition to engaging a wide range of immune systems, it appears to act more quickly and safely against solid tumors.

“CAR‑T cells rely on adaptive immune activation and clonal expansion, leading to potent antitumor responses, but often leading to systemic cytokine release and significant toxicity,” said Shih-Ying Wu. “In contrast, CARMA induces a rapid and self-limiting innate immune response, resulting in strong local tumor control with much less systemic inflammation.”

In a mouse model of brain tumors, genetically engineered MyD88-CARMA cells rapidly slowed tumor growth while exhibiting a strong safety profile. Treated animals maintained normal body weight and liver function and showed no signs of neurological side effects, suggesting that the treatment could effectively attack tumors without causing collateral damage.

In our preclinical studies, the anti-mesothelin CARMA showed potent antitumor activity not only in a lung cancer brain metastasis model, but also in a breast cancer brain metastasis and primary glioblastoma model, demonstrating that CAR macrophages can maintain efficacy across a variety of intracranial tumor types.

—Shih-Ying Wu, Wake Forest University School of Medicine

However, this system is not perfect. The tumor microenvironment is highly heterogeneous, and some tumors may still suppress CARMA activity or bias macrophages toward a pro-tumorigenic phenotype. Researchers are exploring the following strategies: increase sustainability, countering inhibitory signalsimprove Antitumor activity.

Although Wake Forest’s research focuses on brain metastases from lung cancer, its impact extends far beyond a single tumor type. Mesothelin is expressed in several solid tumors, such as pancreatic and ovarian cancers, which also metastasize to the brain in certain circumstances. Additionally, different CAR constructs can be substituted depending on tumor antigen expression, allowing the possibility of targeting different cancers.

“In our preclinical studies, anti-mesothelin CARMA showed potent antitumor activity not only in a lung cancer brain metastasis model, but also in a breast cancer brain metastasis and primary glioblastoma model, demonstrating that CAR macrophages can maintain efficacy across a variety of intracranial tumor types,” said Shih-Ying Wu.

“A major transitional advantage is the flexibility of systemic delivery of CARMA. Unlike CAR-T, which typically requires direct intracranial injection, CARMA can be administered intravenously, intracardially, or intraarterially and still be effectively mobilized to intracranial tumors. This allows the treatment of lesions that are multifocal, invasive, or surgically inaccessible, increasing the clinical utility of CARMA for glioblastoma and other primary brain tumors.” ”

Beyond oncology

Macrophages play a central role in tissue repair and regeneration across multiple organs, including the skin, liver, lungs, kidneys, heart, and intestines. Their phagocytic ability allows them to remove not only cancer cells, but also neurotoxic debris, infectious agents, and pathological protein aggregates. For example, in a neurological setting, CARMA could theoretically be repurposed to eliminate neurological diseases. accumulated toxic substances In certain genetic or neurodegenerative brain disorders.

As with any new cell therapy, significant hurdles remain before CARMA reaches routine clinical use. Manufacturing, persistence, dosing strategies, and long-term safety all need to be carefully evaluated in human trials. Nevertheless, CARMA therapy represents a flexible and potentially transformative platform that can redefine how medicine approaches a variety of difficult diseases.