Liu, Gao, Xi, et al. showed that TREM2⁺ TAMs drive GPC3-CAR-T resistance in hepatocellular carcinoma. Trem2 deletion synergized with CAR-T therapy to enhance effector functionality (with reduced exhaustion in endogenous tumor-specific T cells), metabolically reprogram TAMs toward an antitumor CXCL9hi/SPP1lo phenotype, and achieve durable control in an HCC tumor model. The dual intervention enhanced oxidative metabolism and suppressed glycolysis via AMPK and STAT1 signaling and PI3K–AKT–mTOR inhibition. CD40 agonism phenocopied Trem2 loss, with sotigalimab promoting human CD8⁺ T cell migration and CAR-T responses.
Contributed by Shishir Pant
ABSTRACT: Chimeric antigen receptor (CAR)-T therapy targeting GPC3 shows unsatisfactory clinical efficacy in hepatocellular carcinoma (HCC). Combining clinical data and the immunocompetent orthotopic HCC model, we demonstrate that TREM2(+) tumor-associated macrophages (TAMs) are critical mediators of GPC3-CAR-T resistance. We find that Trem2 deficiency synergizes with GPC3-CAR-T to enhance tumor control by expanding endogenous tumor-specific CD8(+) T cells (not CAR-T amplification) and reeducating TAMs to an anti-tumor CXCL9(hi)/SPP1(lo) phenotype via metabolic reprogramming. Mechanistically, this combination enhances oxidative metabolism while suppressing glycolysis through JAK-STAT1 triggering, AMPK activation, and PI3K-AKT-mTOR inhibition. Crucially, Trem2 deficiency up-regulates CD40 expression, enabling CD40 agonism to phenocopy Trem2-deficiency effects via AMPK activation and STAT1-driven CXCL9 production. Notably, the clinical agonist sotigalimab similarly enhances human CD8(+) T cell migration in vitro. Our findings highlight the significance of combining GPC3-CAR-T therapy with CD40 agonist as a critical pre-requisite for eliciting reeducation of TAMs and enhancing the efficacy of CAR-T therapy in HCC.
Author Info: (1) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Prov
Author Info: (1) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (2) Department of Clinical Laboratory, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510600, China. (3) School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China. (4) The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. (5) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (6) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (7) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (8) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (9) The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. (10) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. (11) The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Clinical Laboratory/State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, China. Electronic address: huangxz020@163.com. (12) The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address: fwzhe@mail.sysu.edu.cn. (13) The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address: tanjzh@mail.sysu.edu.cn.
