Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells

Gal Yagel; Dana Rimini; Michelle von Locquenghien; Roberto Avellino; Oren Barboy; Paulina Chalan; Gaya Granot; Ken Xie; Shir Shlomi-Loubaton; Fadi Sheban; Kfir Mazuz; Eyal David; Pascale Zwicky; Ido Amit

doi:10.1016/j.ccell.2025.11.009

Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells

Gal Yagel
, Dana Rimini
, Michelle von Locquenghien^*
, Roberto Avellino
, Oren Barboy
, Paulina Chalan
, Gaya Granot
, Ken Xie
, Shir Shlomi-Loubaton
, Fadi Sheban
, Kfir Mazuz
, Eyal David
, Pascale Zwicky^*
, Ido Amit^*

^*Corresponding author for this work

Department of Systems Immunology

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies and autoimmune diseases but remains limited in solid tumors due to antigen heterogeneity, escape, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). We developed a macrophage-directed CAR T strategy targeting TREM2⁺ immunosuppressive TAMs, achieving potent in vitro activity and robust antitumor efficacy in vivo. To enhance intratumoral activity, we incorporated synthetic CAR-responsive biosensors containing NFAT, IRF, and AP1 motifs that enable localized IL-12 secretion upon activation. In an immunocompetent human TREM2 transgenic murine model, IL-12-armored hTREM2 CAR T cells remodel the TME and tumor-draining lymph nodes, depleting TREM2⁺ TAMs, enhancing T and natural killer (NK) cell infiltration and activation, and inducing tumor regression without systemic toxicity. This study highlights the potential for developing universal and efficacious CAR T cell therapies targeting tumor-associated macrophages for the treatment of solid tumors.

Original language	English
Journal	Cancer Cell
Early online date	22 Jan 2026
DOIs	https://doi.org/10.1016/j.ccell.2025.11.009
Publication status	Published Online - 22 Jan 2026

Funding

We would like to thank Itay Raveh and Genia Brodsky for their contribution to the visual presentation. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award, funded by the European Union ERC advanced grant (no. 101055341-TROJAN-Cell), European Union (IMMEDIATE EU#: 101095540), the MBZUAI/WIS joint program on artificial intelligence, Lotte and John Hecht Memorial Foundation and the Schwartz Reisman Collaborative Science Program, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 259373024 – TRR 167, the Israel Science Foundation grant no. 1944/22, and the European Union (ERC, MiTE, 101123436). This research was supported by a Research Professorship grant from the Israel Cancer Research Fund, United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel, Ministry of Innovation, Science & Technology (1001703362), Dwek Institute for Cancer Therapy Research, Moross Integrated Cancer Center, EKARD Institute for Cancer Diagnosis Research, Morris Kahn Institute for Human Immunology, Swiss Society Institute for Cancer Prevention Research, Elsie and Marvin Dekelboum Family Foundation, and an ASPIRE Award from The Mark Foundation for Cancer Research, Alzheimer's Association (ABA-25-1373817). This study was supported by the Center for Immunotherapy at the Weizmann Institute of Science. M.v.L. was supported by the National BioInnovators Forum (TEVA Pharmaceuticals), NeuroMac School (CRC/TRR167), and HIDA. P.Z. was supported by the Azrieli International Postdoctoral Fellowship, Koshland Award and the Novartis Foundation for Medical-Biological Research Fellowship.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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10.1016/j.ccell.2025.11.009

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Yagel, G., Rimini, D., von Locquenghien, M., Avellino, R., Barboy, O., Chalan, P., Granot, G., Xie, K., Shlomi-Loubaton, S., Sheban, F., Mazuz, K., David, E., Zwicky, P., & Amit, I. (2026). Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells. Cancer Cell. Advance online publication. https://doi.org/10.1016/j.ccell.2025.11.009

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title = "Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells",

abstract = "Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies and autoimmune diseases but remains limited in solid tumors due to antigen heterogeneity, escape, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). We developed a macrophage-directed CAR T strategy targeting TREM2+ immunosuppressive TAMs, achieving potent in vitro activity and robust antitumor efficacy in vivo. To enhance intratumoral activity, we incorporated synthetic CAR-responsive biosensors containing NFAT, IRF, and AP1 motifs that enable localized IL-12 secretion upon activation. In an immunocompetent human TREM2 transgenic murine model, IL-12-armored hTREM2 CAR T cells remodel the TME and tumor-draining lymph nodes, depleting TREM2+ TAMs, enhancing T and natural killer (NK) cell infiltration and activation, and inducing tumor regression without systemic toxicity. This study highlights the potential for developing universal and efficacious CAR T cell therapies targeting tumor-associated macrophages for the treatment of solid tumors.",

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AU - Yagel, Gal

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AU - von Locquenghien, Michelle

AU - Avellino, Roberto

AU - Barboy, Oren

AU - Chalan, Paulina

AU - Granot, Gaya

AU - Xie, Ken

AU - Shlomi-Loubaton, Shir

AU - Sheban, Fadi

AU - Mazuz, Kfir

AU - David, Eyal

AU - Zwicky, Pascale

AU - Amit, Ido

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N2 - Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies and autoimmune diseases but remains limited in solid tumors due to antigen heterogeneity, escape, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). We developed a macrophage-directed CAR T strategy targeting TREM2+ immunosuppressive TAMs, achieving potent in vitro activity and robust antitumor efficacy in vivo. To enhance intratumoral activity, we incorporated synthetic CAR-responsive biosensors containing NFAT, IRF, and AP1 motifs that enable localized IL-12 secretion upon activation. In an immunocompetent human TREM2 transgenic murine model, IL-12-armored hTREM2 CAR T cells remodel the TME and tumor-draining lymph nodes, depleting TREM2+ TAMs, enhancing T and natural killer (NK) cell infiltration and activation, and inducing tumor regression without systemic toxicity. This study highlights the potential for developing universal and efficacious CAR T cell therapies targeting tumor-associated macrophages for the treatment of solid tumors.

AB - Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies and autoimmune diseases but remains limited in solid tumors due to antigen heterogeneity, escape, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). We developed a macrophage-directed CAR T strategy targeting TREM2+ immunosuppressive TAMs, achieving potent in vitro activity and robust antitumor efficacy in vivo. To enhance intratumoral activity, we incorporated synthetic CAR-responsive biosensors containing NFAT, IRF, and AP1 motifs that enable localized IL-12 secretion upon activation. In an immunocompetent human TREM2 transgenic murine model, IL-12-armored hTREM2 CAR T cells remodel the TME and tumor-draining lymph nodes, depleting TREM2+ TAMs, enhancing T and natural killer (NK) cell infiltration and activation, and inducing tumor regression without systemic toxicity. This study highlights the potential for developing universal and efficacious CAR T cell therapies targeting tumor-associated macrophages for the treatment of solid tumors.

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DO - 10.1016/j.ccell.2025.11.009

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SN - 1535-6108

JO - Cancer Cell

JF - Cancer Cell

ER -

Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells

Abstract

Funding

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