DHX58/LGP2 and L-selectin/CD62L mark a stem-like T-cell state associated with immune checkpoint blockade responsiveness in gastric cancer

Immune checkpoint inhibitors (ICIs) have expanded treatment options for gastric cancer (GC), but the molecular features supporting persistent antitumour T-cell activity remain incompletely defined. We investigated whether DHX58/LGP2 and SELL-encoded L-selectin/CD62L mark a stem-like T-cell state associated with ICI responsiveness. Nine autologous GC patient-derived organoid–tumour-infiltrating lymphocyte (PDO–TIL) models were evaluated under defined single or combined ICI conditions. PDO growth, T-cell phenotypes, cytokine secretion, and paired T-cell and tumour-cell bulk RNA sequencing were assessed. CD62L-positive T cells isolated after effective coculture were rechallenged with previously untreated matched PDOs. An independent clinical single-cell RNA-sequencing dataset (GSE315928) and post-treatment GC tissues were analysed for external validation. CD62L-positive T-cell abundance was inversely associated with PDO growth (Spearman’s r = − 0.70) and increased after effective coculture. During head-to-head PDO rechallenge, CD62L-positive T cells showed the greatest short-term expansion, tumour control, and effector release compared with CD62L-negative and unsorted total CD3-positive T cells. Effective conditions were accompanied by increased SELL , TCF7 , LEF1 , and BACH2 expression and reduced IRF4 expression, consistent with a less-differentiated, persistence-associated programme. Isolated CD62L-positive T cells retained cytotoxic activity against untreated matched PDOs and secreted increased IFN-γ, TNF-α, and granzyme B upon rechallenge. In the clinical dataset, SELL-positive stem-like T cells were enriched in post-treatment responders and showed higher DHX58 expression. Multiplex immunohistochemistry further supported greater representation of DHX58 -positive CD62L-positive T cells in responder tissues. Inferred ligand–receptor analysis suggested communication between CD44-positive tumour cells and SELL-positive stem-like T cells. DHX58/LGP2 and L-selectin/CD62L represent complementary features of a functionally active, stem-like T-cell state associated with ICI responsiveness in GC. These findings support a molecular association rather than a direct regulatory relationship and warrant prospective and mechanistic validation.