Beyond T cell exhaustion: TIM-3 regulation of myeloid cells

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an important immune checkpoint molecule initially identified as a marker of IFN-γ-producing CD4⁺ and CD8⁺ T cells. Since then, our understanding of its role in immune responses has significantly expanded. Here, we review emerging evidence demonstrating unexpected roles for TIM-3 as a key regulator of myeloid cell function, in addition to recent work establishing TIM-3 as a delineator of terminal T cell exhaustion, thereby positioning TIM-3 at the interface between fatigued immune responses and reinvigoration. We share our perspective on the antagonism between TIM-3 and T cell stemness, discussing both cell-intrinsic and cell-extrinsic mechanisms underlying this relationship. Looking forward, we discuss approaches to decipher the underlying mechanisms by which TIM-3 regulates stemness, which has remarkable potential for the treatment of cancer, autoimmunity, and autoinflammation.