GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307934/primary200OKTranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307934GEOGSEfalseSingle-cell RNA sequencing of orthotopic pancreasic cancer reveals characterization of tumor microenvironment by treatment of anti-VSIG4 antibodies in KPC cell transplantation mouse modelImmune checkpoint blockade (ICB) therapies, such as PD-1/PD-L1 inhibitors, have revolutionized cancer treatment by reactivating exhausted T cells. However, their efficacy varies substantially among tumor types and is particularly limited in immunologically “cold” malignancies such as pancreatic ductal adenocarcinoma. These tumors exhibit minimal T-cell infiltration and a profoundly immunosuppressive tumor microenvironment (TME), leading to poor responses to ICB. VSIG4 is a B7-related transmembrane protein highly expressed by tissue-resident macrophages. Previous studies have shown that VSIG4 suppresses proinflammatory macrophage polarization by modulating pyruvate metabolism and enhances M2-like states via lactate-STAT3 signaling and fatty acid oxidation. VSIG4 also inhibits T-cell activation and proliferation, making it a candidate immune checkpoint molecule. Recent work has linked VSIG4⁺ tumor-associated macrophages to T-cell suppression and therapeutic resistance in multiple cancers, although the identity of the T-cell receptor for VSIG4 remains unknown. So we demonstrate that VSIG4 binds SLC3A2 to suppress Gln uptake and disrupt ion homeostasis, thereby impairing T-cell activation. Antibody-mediated VSIG4 blockade restores T-cell function and induces robust antitumor responses, especially in pancreatic cancer models. These findings define a novel VSIG4–SLC3A2 axis that integrates metabolic and ionic control to suppress immunity, offering a promising strategy to overcome resistance in “cold” tumors.2026/06/18GSE307934GSM9234297GSM9234296GSM9234299GSM9234298GSM9234295GSM923429428330307934Mus musculus[42259604]