[New York, NY [January 22, 2026]—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 going after cancer cells directly, it targets the cells that protect them.
The study, published in the January 22 online issue of Cancer Cell, a Cell Press Journal [DOI 10.1016/j.ccell.2025.12.021], was conducted in aggressive preclinical models of metastatic ovarian and lung cancer. It points to a new strategy for treating advanced-stage solid tumors.
In a strategy modeled after the famed Trojan horse, the treatment enters the tumors by targeting cells called macrophages that guard the cancer cells, disarms these protectors, and opens up the tumor's gates for the immune system to enter and wipe out the cancer cells.
Metastatic cancers cause the vast majority of cancer-related deaths, and solid tumors such as lung and ovarian cancer have proven especially difficult to treat with current immunotherapies. One major reason is that tumors actively suppress the immune system in their immediate surroundings, creating a kind of protective fortress around the cancer cells, say the investigators.
"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."
Those protective cells are tumor macrophages. In healthy tissues, macrophages act as first responders, fighting infection and helping to repair damage. Inside tumors, however, the macrophages are reprogrammed to do the opposite, blocking immune attack and helping cancer survive and spread.
The research team designed a therapy to specifically eliminate the tumor macrophages, while sparing the normal ones, and converting the tumor from immune-suppressed to immune-active. The approach uses engineered immune cells, known as CAR T cells, derived from a patient's own T cells. Normally, CAR T cells are designed to recognize and kill cancer cells, but for many types of cancers there are not good ways to make the CAR T cells do that. Therefore, the team designed the CAR T cells to recognize the tumor's macrophages.
They further engineered the CAR T cells to produce a potent immune-activating molecule called interleukin-12, which is specialized at turning on killer T cells. When they treated mice that had metastatic lung and ovarian cancers with their CAR T cells, the results were striking, with the mice surviving for months longer and many being completely cured by the treatment.
To understand what was happening inside the tumors, the team used advanced spatial genomics techniques. These analyses showed that the therapy reshaped the tumor environment, removing immune-suppressing cells and drawing in immune cells capable of killing the cancer. This is an important development because it makes the therapy 'antigen-independent' and has the potential to enable many different cancers to be treated, even ones not traditionally amenable to immunotherapy. The same treatment approach successfully treated both lung and ovarian cancers, highlighting its potential as a broad cancer therapy, say the researchers.
"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."
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 viewed as a cure, but as proof of concept for a new immunotherapy strategy.
"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 working to refine the approach, particularly by tightening control over where and how IL-12 is released within tumors in mouse models. The goal is to maximize effectiveness while ensuring safety as the therapy moves closer to potential testing in humans. 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 support cells rather than cancer cells alone.
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.
See the journal paper for details on conflicts of interest: [DOI: 10.1016/j.ccell.2025.12.021].
