Fig. 2

Regulation and functions of Tim-3 in HCC. Cytokines, such as IL-2, IL-7, IL-12, IL-17, TGF-β, and tumor-derived exosomes induce Tim-3 expression in T cells. Tim-3+ T cells present exhaustion phenotypes and reduced production of IFN-γ, IL-2, and TNF-α, indicating impaired anti-tumor immunity. Binding of Gal-9 to Tim-3+ effector T cells further mediates effector T cell apoptosis. Tim-3+ Tregs exert greater suppressor functions, producing reduced IFN-γ and IL-2 as well. Gal-9-expressing cells, including TAMs and DCs, are involved in the interaction of Gal-9 with Tim-3, further leading to Tim-3+ T cell exhaustion and apoptosis. HCC-derived TGF-β upregulates Tim-3 expression on TAMs and Tim-3 overexpression then facilitates M2 polarization of TAMs, further promoting HCC growth, migration, and invasion by the IL-6 pathway. Tim-3 on HCC cells promotes HCC proliferation, migration, and invasion in an IL-6 autocrine manner