TIM-3, an emerging myeloid checkpoint with potential roles in macrophage polarization and immune evasion in gastric cancer

Immune checkpoint blockade has advanced treatment for gastric cancer (GC); however, low response rates and acquired resistance persist due to the tumor-associated macrophage (TAM)-dominated immunosuppressive microenvironment.T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is a potential myeloid checkpoint that regulates immune-barrier development in the tumor microenvironment.By integrating single-cell RNA sequencing and bulk transcriptomic data with pan-cancer mechanistic evidence, we re-evaluate the role of TIM-3 to clarify its potential roles in TAM polarization.Upon galectin-9 ligation, TIM-3 signaling may trigger HLA-Bassociated transcript 3 release and Fyn recruitment, which may activate nuclear factor kappa B, interleukin-6/signal transducer and activator of transcription 3, and phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin cascades to promote M2-like TAM polarization.Most mechanistic evidence is extrapolated from non-GC models.Transcriptomic analyses show TIM-3 co-expression in specifically secreted phosphoprotein 1 positive and complement C1q A chain positive TAM subsets in GC, which may promote the formation of fibrotic and metabolic barriers, thereby trapping CD8 + T cells in peritumoral stroma to create an immune-excluded microenvironment.We appraise clinical strategies targeting TIM-3, compare monoclonal antibodies with tissuepermeable small-molecule inhibitors and matrix-normalizing combinations, and propose a dynamic model of TIM-3-driven adaptive resistance following programmed cell death protein 1 blockade.Targeting the TIM-3/myeloid axis may dismantle the immuneexcluded barrier and enhance GC immunotherapy, but further GC-specific mechanistic and clinical validation is necessary.