Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2026 Jan 22:S1535-6108(25)00555-0.
doi: 10.1016/j.ccell.2025.12.021. Online ahead of print.

Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth

Jaime Mateus-Tique  1 , Ashwitha Lakshmi  1 , Bhavya Singh  1 , Rhea Iyer  1 , Alfonso R Sánchez-Paulete  1 , Chiara Falcomatà  1 , Matthew Lin  2 , Gvantsa Pantsulaia  3 , Alexander Tepper  1 , Trung Nguyen  1 , Angelo Amabile  1 , Gurkan Mollaoglu  1 , Luisanna Pia  1 , Divya Chhamalwan  1 , Jessica Le Berichel  4 , Hunter Potak  5 , Marco Colonna  6 , Alessia Baccarini  1 , Joshua Brody  7 , Miriam Merad  8 , Brian D Brown  9
Affiliations

Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth

Jaime Mateus-Tique et al. Cancer Cell. .

Abstract

Tumor-associated macrophages (TAMs), which commonly express FOLR2 or TREM2, are enriched in solid tumors and keep the tumor microenvironment (TME) immunosuppressed. Here, we introduce IL-12-expressing CAR-T cells targeting FOLR2 or TREM2 to deplete pro-tumor TAMs and reprogram the TME. Treatment with IL-12-armored anti-TAM CAR-T leads to significantly improved survival in metastatic ovarian and lung cancer models. The CAR-T mediates benefit at low cell dose and without lymphodepletion, and remains largely restricted to tumors with no overt toxicity. Spatial transcriptomics reveals that IL-12 anti-TAM CAR-T mediates sustained remodeling of the TME, even after CAR-T contraction, with the expansion of CXCL9+ immunostimulatory macrophages and endogenous tumor-specific cytotoxic T cells. Tumor clearance depends, in part, on FAS expression on cancer cells, revealing an IL-12-FAS axis for IL-12-armored CAR-T activity. These findings position IL-12-producing, myeloid-directed CAR-T as a broad strategy to remodel the TME and drive anti-tumor immunity for solid cancers.

Keywords: CAR T cells; FOLR2; IL-12; TREM2; anti-macrophage therapy; cancer immunotherapy; lung cancer; ovarian cancer; tumor-associated macrophages.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests M.M serves on the scientific advisory board and holds stock (<5%) from Compugen Inc., Myeloid Therapeutics Inc., Asher Bio Inc., Dren Bio Inc., Oncoresponse Inc., Owkin Inc., OSE Inc., DemBio, Inc., and Larkspur Inc. M.M serves on the scientific advisory board of Innate Pharma Inc., Genenta Inc. B.D.B. is on the advisory board of Noetik and Asgard Therapeutics and serves as a consultant for Merck. M.M, B.D.B and J.M.T have submitted a patent on IL-12.aTREM2.CAR constructs and their derivatives. M. Colonna is a member of the Vigil Neuro scientific and Cell Signaling Technology advisory boards, received research grants from Vigil Neuro during the conduct of the study, and has a patent to TREM2 pending (PCT/US2021/019914).

LinkOut - more resources