Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and destroy tumors. Approaches such as immune checkpoint inhibitors and engineered immune cells have produced durable responses in some patients, none more dramatic than CAR T cell therapy in blood cancers. Several CAR-T treatments are currently approved by the FDA and have resulted in long-term remissions. leukemia and lymphoma.

But that success is much harder to replicate solid tumor.

Unlike blood cancers, solid tumors create a hostile microenvironment that actively blocks immune attack. Modified T cells often have a hard time infiltrating tumors, surviving long enough to become active, or maintaining function once inside. As a result, researchers are shifting their focus from cancer cells to the immune ecosystem that surrounds and protects cancer cells.

in new research Published in cancer cellsresearchers described an experimental immunotherapy that targets tumor-associated macrophages (TAMs) rather than cancer cells themselves, dismantling the immune shield that allows tumors to evade attack.

Tumors are more than cancer cells

“What we call a tumor is actually a cancer cell surrounded by cells that nourish and protect it,” he said. Jaime Mateus-TikeHe is one of the lead authors of this study. news release. “It’s a fortress surrounded by walls.”

TAMs are one of the most abundant immune cells in solid tumors; 50 percent Percentage of immune cell populations within the tumor microenvironment (TME). Macrophages typically serve as first responders to infection and tissue damage, and tumors engulf them. reprogram these cells Suppresses immune activity and supports tumor growth and metastasis.

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“If you look at a tissue section of an ovarian tumor or a lung tumor, you can see that it’s filled with macrophages.” brian brownsaid the director of the Icahn Institute for Genomics and the study’s lead author. DDN. “Our hypothesis was that by removing the cells that protect the cancer cells, endogenous killer T cells would be able to eliminate the cancer cells.”

There is another reason to target macrophages rather than cancer cells. “Cancer cells don’t express many molecules that are different from the cells they come from,” says Professor Brown. “So creating CAR T cells that target molecules expressed by cancer cells risks killing healthy cells that express the same molecules.”

In contrast, for many years tumor profiling revealed that TAMs upregulate certain markers, such as FOLR2 (folate receptor 2) and TREM2 (trigger receptor expressed on myeloid cells 2), which are less common in normal macrophages.

“We wanted to generate CAR T cells that primarily target these molecules expressed by macrophages within tumors,” Brown says. “CAR T cells can invade tumors like a Trojan horse.”

trojan horse strategy

This strategy is not entirely new. Previous efforts using macrophage-targeted CAR T cells have shown promise in preclinical models. However, the effect does not last long and the tumor eventually rebounds. Based on previous findings that interferon gamma (IFNγ) release is a key driver of anti-macrophage CAR T activity, the Mount Sinai team set out to fortify, or “protect”, these cells to make their effects more lasting.

To do this, the researchers engineered TAM-targeted CAR T cells expressing FOLR2 or TREM2 and programmed them to secrete IL-12 (interleukin 12), a potent immune-activating cytokine. IL-12 activates T cells and promotes IFNγ production. IFNγ is a cytokine that not only promotes T cell killing but also reprograms macrophages toward an anticancer immunostimulatory state.

“What’s unique about our approach is that we kill the macrophages so that their replacements don’t become immunosuppressed again,” Brown says. “They become immunostimulatory macrophages. This causes a self-sustaining reprogramming of the tumor microenvironment.”

Reconstruction of TME

To understand how this therapy changes tumors from within, the researchers turned to spatial transcriptomics, along with flow cytometry and multiplexed imaging.

“The change was not subtle,” Brown said. In treated tumors, cancer cells were almost completely eliminated. However, the most notable difference was in their immune status.

Spatial genomics revealed that after 10 days of treatment, the tumors displayed a completely different immune architecture. “Instead of expressing immunosuppressive molecules, the macrophages expressed highly immunostimulatory anti-cancer molecules such as MHC class I, CD40, TNF, and CYBB,” Brown said. At the same time, the number of cytotoxic CD8+ T cells, the immune system’s main cancer cells, increased more than threefold.

These immune changes have had remarkable consequences in preclinical models. Mice with metastatic lung and ovarian cancers survived months longer after treatment, and many were completely cured.

Broad approach

One of the most attractive aspects of this strategy is its potential to be effective against many different types of cancer. Because this treatment targets the immune cells that surround and protect tumors, rather than the cancer cells themselves, it may be effective even in cancers that lack clear targetable tumor antigens.

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This difference is important because CAR T cells are not designed to directly kill cancer cells. Instead, it destroys the tumor’s protective barrier and frees the host’s immune system to eliminate the disease. Dr. Brown explained, “In data not included in the paper, we found that we could reintroduce the cancer cells to the surviving mice, and they quickly eliminated the cancer cells. This is a hallmark of immune memory, and since the animals no longer have CAR T cells, they must come from the host’s immune system.”

The research team is now working to refine the approach, particularly by controlling where and how IL-12 is released within the tumor, to maximize efficacy while maintaining safety. Beyond lung and ovarian cancers, the researchers believe this strategy could serve as the basis for future CAR T therapies that target supporting cells rather than cancer cells alone to reshape tumors.