Targeting TREM1: screening metabolically-active TCM compounds for TAM polarization and enhancing PD-1 inhibitor efficacy in HCC by alleviating immunosuppression

doi:10.5246/jcps.2026.05.030

Abstract

Abstract:

Hepatocellular carcinoma (HCC), characterized by its high malignancy, poses a serious threat to patient survival and health. Immunotherapy has increasingly emerged as a key therapeutic strategy for HCC; however, the immunosuppressive tumor microenvironment (TME) frequently undermines its efficacy. Therefore, identifying molecular targets and therapeutic agents capable of alleviating this immunosuppression is of paramount importance. In this study, bioinformatics analyses revealed that triggering receptor expressed on myeloid cells-1 (TREM1) expression correlated positively with HCC progression, and elevated TREM1 levels were associated with poorer clinical outcomes. Notably, TREM1 was predominantly expressed in macrophages and exhibited the strongest interaction with these cells within the TME. Functional in vitro assays demonstrated that silencing TREM1 attenuated the immunosuppressive phenotype of tumor-associated macrophages (TAMs). In a subcutaneous mouse tumor model, TREM1 knockdown synergized with PD-1 blockade to enhance anti-tumor efficacy. RNA sequencing further indicated that TREM1 modulated metabolism-related pathways. Complementary literature review and molecular docking analyses suggested that specific bioactive compounds derived from traditional Chinese medicine (TCM) might exert anti-HCC effects by targeting TREM1 and regulating TAM metabolism. Collectively, these findings provided a novel mechanistic framework for understanding the immunomodulatory potential of TCM in HCC therapy.

Key words: Hepatocellular carcinoma, Tumor-associated macrophages, Traditional Chinese medicine, PD-1, TREM1, Immunosuppression, Tricarboxylic acid cycle

Supporting:

Ruiwei Yao, Ziyi Zeng, Yue He, Ying Zhang, Chong Zhong, Jinfang Zhang. Targeting TREM1: screening metabolically-active TCM compounds for TAM polarization and enhancing PD-1 inhibitor efficacy in HCC by alleviating immunosuppression[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(5): 420-437.

Figures/Tables 11

Table 1. Primer sequence information.

Table 2. A summary of TCM active components with metabolic regulatory functions over the past 3 years.

Table 3. Molecular docking results.

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