Single-cell transcriptomics reveals CD8 + T-cell heterogeneity linked to immunotherapy response in gastric cancer.

Abstract

Immune checkpoint blockade elicits durable responses in a subset of patients with gastric cancer, yet the cellular programs underlying therapeutic divergence remain unclear. Using integrative single-cell transcriptomics of tumors from Immune Checkpoint Inhibitor (ICI)-treated patients, we resolved the CD8 + T-cell landscape associated with response. Therapeutic outcome reflected not only differences in state abundance but also functional reprogramming within shared states. Trajectory analysis revealed bifurcation of naïve CD8 + T cells into effector and exhaustion-prone branches that were differentially enriched between responders and non-responders. Inference of transcription factor activity revealed lineage-specific modules associated with these divergent fates. Further modeling of ligand-receptor pairs uncovered how signaling between myeloid and T cells changes during different responses. Together, these findings delineate a regulatory and intercellular framework characterizing CD8 + T-cell differentiation in gastric cancer and illuminate mechanisms of immune-state divergence during immunotherapy.