GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330011/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330011GEOGSEfalseRegulatory T cells Restrain CD4 T Cell Control of MHC-I-Deficient Metastatic Pancreatic Cancer Emerging After PD-L1 Blockade [scRNA-seq]We investigate mechanisms of immunotherapy resistance in pancreatic cancer. PD-L1 blockade selects for metastatic tumor variants with defective IFNγ-inducible MHC-I due to epigenetic silencing of Tap1. Restoring MHC-I limits primary tumor growth but fails to prevent metastasis. In contrast, regulatory T cell (TREG) depletion suppresses metastasis by unleashing CD4 T helper cells. Adoptive transfer of tumor-specific CD4 T cells impairs metastatic progression. Tumor-specific CD4 T cells in lymph nodes preferentially adopt a TCF1⁺SLAMF6⁺ precursor state. Intratumoral TREG targeting with anti–CTLA-4 abrogates metastasis, drives accumulation of stem-like, tissue-resident helper CD4 T cells, producing a gene signature associated with improved patient outcomes. Combined CTLA-4 blockade and MHC-I restoration eliminates metastasis and prolongs animal survival. In human tumors, TREG and CD4 helper T cells co-localize and correlate with both tumor MHC-I expression and overall survival. Together, these findings identify actionable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer.2026/06/26GSE330011GSM9715165GSM971516634328330011Mus musculus