Galectin-3 and TREM2: a myeloid axis as a predictive biomarker for immune checkpoint inhibitors in cancer

The ligand-receptor relationship between Galectin-3 and TREM2 has been identified in lung cancer. High expression of both is associated with anti-PD-1 efficacy, suggesting that the combination of both may predict the benefit of immune checkpoint inhibitors (ICIs). This review comprises five sections presenting the structure/expression, interaction, immunomodulatory roles, spatial profiling, and clinical application of Galectin-3/TREM2. The carbohydrate-recognition domain (CRD) of Galectin-3 and the immunoglobulin (Ig) domain of TREM2 are the Galectin-3-TREM2 interaction domains. Galectin-3 is mainly secreted by tumor cells, stromal cells and tumor-associated macrophages (TAMs), while TREM2 is expressed on myeloid cells, especially macrophages. Galectin-3 and TREM2 reduce T cell and NK cell function, promote M2 polarization of macrophages, and remodel the myeloid microenvironment. Both Galectin-3 and TREM2 show potential in predicting ICI benefit in lung cancer, but prediction studies combining Galectin-3 and TREM2 have not yet been reported. Preclinical evidence supports that Galectin-3/TREM2 dual inhibition can suppress tumor progression in lung cancer models. In clinical studies, Galectin-3 inhibitors Belapectin and GB1211 show acceptable safety, and Belapectin plus pembrolizumab shows certain efficacy in solid tumors. However, the TREM2 inhibitor PY314 showed limited efficacy in renal cell carcinoma, suggesting the need for improved antibody design and better patient selection. We present a comprehensive overview of the role of Galectin-3/TREM2 in cancer, suggesting novel strategies for predicting ICI benefit.