Fig. 5: HVEM mediates TNK2-induced CD8⁺ T cell dysfunction.

a Venn diagram illustrating the screening strategy for TNK2-regulated cell surface proteins. Candidate genes were obtained from the intersection of four datasets: immune-regulatory proteins, known membrane proteins, proteins with significant membrane peptides identified by surface proteomics after TNK2 overexpression, and genes upregulated in PDAC with fold change ≥2. Six overlapping genes (HVEM, PPIA, GPI, PSMC2, CALR, and RAC1) were identified. b ScRNA-seq data analysis, UMAP plot were annotated and colored for different cell types (left panel). Expression levels of TNK2 and HVEM were lighted in UMAP individually (2 middle panels) or together (right panel). c Hierarchical plot showing the inferred intercellular communication network for HVEM signaling. Solid and open circles represent source and target, respectively. Circle edge width represents the communication probability. Edge colors are consistent with the signaling source. d Heatmap showing the relative importance of each cell group based on the computed four network centrality measures (Sender, Receiver, Mediator, Influencer) of HVEM signaling pathway network. Representative pancreatic tumor images (e, j) and tumor size measured at the experimental endpoint (f, k) in tumors formed by KPC#3 cells expressing TNK2 cDNA or vector (e, f) or KPC#1 cells expressing TNK2 shRNA or control (j–k). Flow cytometry analysis showing the changes of CD8⁺ T cells (g, l), TNFα⁺CD8⁺ T cells (h, m), and PD-1⁺CD8⁺ T (i, n) cells in tumors formed by KPC#3 cells expressing TNK2 cDNA or vector (g–i) or KPC#1 cells expressing TNK2 shRNA or control (l–n). Statistical significance was determined by two-way ANOVA followed by Tukey’s multiple comparisons test (f, k) and one-way ANOVA followed by Tukey’s multiple comparisons test (g–i, l–n). n = 8 independent experiments (e–n). All tests were two sided. Data represent as mean ± s.d. Source data are provided as a Source Data file.