Scientists at the Icahn School of Medicine at Mount Sinai have developed an experimental immunotherapy that takes an unconventional approach to metastatic cancer: instead of directly targeting cancer cells, it targets the cells that protect them.
The study, published in the January 22 online issue of Cancer Cella Cell Press Journal [DOI 10.1016/j.ccell.2025.12.021]was conducted in aggressive preclinical models of metastatic ovarian and lung cancer. It indicates a new strategy for the treatment of advanced solid tumors.
In a strategy modeled after the famous Trojan horse, the treatment enters tumors by targeting cells called macrophages that protect cancer cells, disarms these prostates and opens the tumor’s floodgates for the immune system to enter and destroy the cancer cells.
Metastatic cancers cause the vast majority of cancer-related deaths, and solid tumors such as lung and ovarian cancer have proven particularly difficult to treat with current immunotherapies. One m
The main reason is that tumors actively suppress the immune system in their immediate environment, creating a kind of protective fortress around the cancer cells, the researchers say.
What we call a tumor are actually cancer cells surrounded by cells that nourish and protect them. It is a walled fortress. With immunotherapy, we continued to face the same problem – we can’t get past the guards of this fortress. So we thought: what if we targeted these guards, turned them from patrons to friends, and used them as a gateway to bring a wreckage force into the fortress.”
Jaime Mateus-Tique, PhD, lead study author, faculty member in Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai
These protective cells are tumor macrophages. In healthy tissues, macrophages act as first responders, fighting infection and helping to repair damage. Inside tumors, however, macrophages are reprogrammed to do the opposite, blocking the immune attack and helping the cancer survive and spread.
The research team designed a treatment to specifically eliminate tumor macrophages while sparing normal ones and converting the tumor from immunosuppressed to immunoactive. The approach uses engineered immune cells, known as CAR T cells, derived from the patient’s own T cells. Normally, CAR T cells are designed to recognize and kill cancer cells, but for many types of cancer there are no good ways to get CAR T cells to do this. Therefore, the team engineered the CAR T cells to recognize tumor macrophages.
They further engineered the CAR T cells to produce a powerful immunostimulatory molecule called interleukin-12, which is specialized in activating killer T cells. When they treated mice that had metastatic lung and ovarian cancer with the CAR T cells, the results were impressive, with the mice surviving for months longer and many being completely cured of the treatment.
To understand what was happening inside the tumors, the team used advanced spatial genomics techniques. These analyzes showed that the treatment reshaped the tumor environment, removing immune-suppressing cells and pumping in immune cells capable of killing the cancer. This is an important development because it makes therapy “antigen-independent” and has the potential to enable the treatment of many different cancers, even those not traditionally amenable to immunotherapy. The same therapeutic approach successfully treated both lung and ovarian cancer, highlighting its potential as a broad-based cancer treatment, the researchers say.
“Macrophages are found in every type of tumor, sometimes outnumbering cancer cells. They exist because the tumor uses them as a shield,” says senior author Brian Brown, PhD, Director of the Icahn Genomics Institute, Vice President of Immunology and Immunotherapy, Associate Director of the Marc and Jennifer Lipschultz Institute, Institute for Precision Engineering at Simmunetic. Icahn School of Medicine at Mount Sinai. “What’s so exciting is that our treatment turns these cells from protecting the cancer to killing it. We’ve turned the enemy into an ally.”
The researchers stress that human studies are needed to determine whether the approach will be safe and effective in patients. The results should not be considered a cure, but rather a proof of concept for a new immunotherapy strategy.
“This establishes a new way of treating cancer,” says Dr. Brown. “By targeting tumor macrophages, we have shown that it is possible to eliminate cancers that are resistant to other immunotherapies.”
The team is now working to improve the approach, particularly by increasing control over where and how IL-12 is released in tumors in mouse models. The goal is to maximize efficacy while ensuring safety as the treatment moves closer to potential human trials. Beyond lung and ovarian cancer, the researchers believe the strategy could serve as a foundation for future CAR T therapies that reshape tumors by targeting their supporting cells, not just cancer cells.
The paper is titled “Shielded macrophage-targeted CAR-T cells restore and reprogram the tumor microenvironment and control metastatic cancer growth.”
The authors of the study, as reported in the journal, are Jaime Mateus-Tique, Ashwitha Lakshmi, Bhavya Singh, Rhea Iyer, Alfonso R. Sánchez-Paulette, Chiara Falcomata, Matthew Lin, Gvantsa Pantsulaia, Alexander Tepper, Trung Amabnailea, AngeloGuyen, Divya Chhamalwan, Jessica Le Berichel, Hunter Potak, Marco Colonna, Alessia Baccarini, Joshua Brody, Miriam Merad and Brian D. Brown.
The work was supported by grants from the NIH (U01CA28408, R01CA254104), the Cancer Gene Therapy Alliance, the Feldman Family Foundation, and the Applebaum Foundation.
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