魏茨曼科学研究所Ido Amit课题组在研究中取得进展。他们开发出装甲巨噬细胞靶向抗TREM2 CAR-T细胞对实体肿瘤的非肿瘤抗原靶向作用。2026年1月22日出版的《癌细胞》发表了这项成果。

研究组开发了一种针对TREM2⁺免疫抑制TAMs的巨噬细胞靶向CAR - T策略，获得了有效的体外活性和体内抗肿瘤效果。为了增强肿瘤内活性，该课题组人员合成了含有NFAT、IRF和AP1基元的CAR响应生物传感器，这些基元能够在激活时局部分泌IL-12。在免疫能力强的人TREM2转基因小鼠模型中，IL-12装甲hTREM2 CAR - T细胞重塑TME和肿瘤引流淋巴结，消耗TREM2⁺ TAMs，增强T细胞和自然杀伤细胞（NK）的浸润和活化，诱导肿瘤消退，无全身毒性。这项研究强调了开发针对肿瘤相关巨噬细胞的通用和有效的CAR - T细胞疗法治疗实体瘤的潜力。

据介绍，嵌合抗原受体（CAR） T细胞治疗在血液恶性肿瘤和自身免疫性疾病中显示出显著的成功，但由于抗原异质性、逃逸和由肿瘤相关巨噬细胞（TAMs）主导的免疫抑制肿瘤微环境（TME），在实体肿瘤中仍然受到限制。

附：英文原文

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

Author: 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

Issue&Volume: 2026-01-22

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.

DOI: 10.1016/j.ccell.2025.11.009

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00502-1