Scientists at the Icahn School of Medicine at Mount Sinai have created an experimental immunotherapy that approaches metastatic cancer from a different angle. Rather than attacking cancer cells directly, the treatment focuses on the cells that surround and protect them.
The research, published in the January 22 online issue of Cancer Cell, a Cell Press Journal, tested the strategy in aggressive preclinical models of metastatic ovarian and lung cancer. The findings suggest a promising new direction for treating advanced solid tumors that have resisted existing therapies.
Using Cancer’s Defenses as a Way In
The approach is inspired by the Trojan horse. Instead of forcing its way into tumors, the therapy enters by targeting macrophages, immune cells that act as guardians for cancer cells. By disabling these protective cells, the treatment opens the tumor to attack, allowing the immune system to move in and destroy the cancer.
Metastatic disease accounts for most cancer-related deaths, and solid tumors such as lung and ovarian cancer are particularly hard to treat with current immunotherapies. According to the researchers, one key reason is that tumors suppress immune activity in their immediate environment, creating a powerful barrier that shields cancer cells from attack.
“What we call a tumor is really cancer cells surrounded by cells that feed and protect them. It’s a walled fortress,” says lead study author Jaime Mateus-Tique, PhD, a faculty member in Immunology and Immunotherapy at the Icahn School of Medicine at Mount Sinai. “With immunotherapy, we kept running into the same problem — we can’t get past this fortress’s guards. So, we thought: what if we targeted these guards, turned them from protectors to friends, and used them as a gateway to bring a wrecking force within the fortress.”
How Tumor Macrophages Help Cancer Survive
Those guards are tumor-associated macrophages. In healthy tissue, macrophages serve as early responders, helping fight infections and repair damage. Inside tumors, however, these same cells are reprogrammed to suppress immune responses, support cancer growth, and aid the spread of disease.
The Mount Sinai team designed a therapy that selectively removes tumor macrophages while leaving healthy macrophages intact. By doing so, the treatment shifts the tumor environment from immune-suppressed to immune-active.
Reengineering CAR T Cells for a New Target
The therapy relies on CAR T cells, engineered immune cells made from a patient’s own T cells. CAR T treatments are typically designed to recognize and kill cancer cells directly, but for many solid tumors, suitable cancer targets have been difficult to identify. To overcome this challenge, the researchers redirected CAR T cells to recognize tumor macrophages instead.
The team also modified the CAR T cells to release interleukin-12, a powerful immune-stimulating molecule that activates killer T cells. When mice with metastatic lung and ovarian cancer were treated with the engineered cells, the results were dramatic. The animals lived months longer than untreated mice, and many were completely cured.
Reshaping the Tumor Environment
To see how the therapy worked inside tumors, the researchers used advanced spatial genomics techniques. These analyses revealed that the treatment transformed the tumor environment by removing immune-suppressing cells and attracting immune cells capable of killing cancer.
This shift is especially important because it makes the therapy ‘antigen-independent’, meaning it does not rely on identifying specific cancer cell markers. As a result, the strategy could potentially be applied to many different cancers, including those that have not responded well to traditional immunotherapy. The same approach proved effective in both lung and ovarian cancer models, underscoring its potential as a broadly applicable treatment.
“Macrophages are found in every type of tumor, sometimes outnumbering the cancer cells. They’re there because the tumor uses them as a shield,” says senior author Brian Brown, PhD, Director of the Icahn Genomics Institute, Vice Chair of Immunology and Immunotherapy, Associate Director of the Marc and Jennifer Lipschultz Precision Immunology Institute, and Mount Sinai Professor of Genetic Engineering, at the Icahn School of Medicine at Mount Sinai. “What’s so exciting is that our treatment converts these cells from protecting the cancer to killing it. We’ve turned foe into ally.”
What Comes Next
The researchers emphasize that studies in humans are still needed to determine whether the therapy is safe and effective for patients. The results should be seen as proof of concept rather than a cure.
“This establishes a new way to treat cancer,” says Dr. Brown. “By targeting tumor macrophages, we’ve shown that it can be possible to eliminate cancers that are refractory to other immunotherapies.”
The team is now refining the approach, with a focus on controlling where and how IL-12 is released within tumors in mouse models. Their goal is to maximize the therapy’s impact while maintaining safety as it moves closer to potential human testing. Beyond lung and ovarian cancer, the researchers believe this strategy could form the basis for future CAR T therapies that reshape tumors by targeting their support cells, not just cancer cells themselves.
The paper is titled “Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth.”
The study’s authors, as listed in the journal, are Jaime Mateus-Tique, Ashwitha Lakshmi, Bhavya Singh, Rhea Iyer, Alfonso R. Sánchez-Paulete, Chiara Falcomata, Matthew Lin, Gvantsa Pantsulaia, Alexander Tepper, Trung Nguyen, Angelo Amabile, Gurkan Mollaoglu, Luisanna Pia, Divya Chhamalwan, Jessica Le Berichel, Hunter Potak, Marco Colonna, Alessia Baccarini, Joshua Brody, Miriam Merad, and Brian D. Brown.
The work was supported by NIH grants (U01CA28408, R01CA254104), the Alliance for Cancer Gene Therapy, the Feldman Family Foundation, and the Applebaum Foundation.
