The study investigates the mechanisms behind the ineffectiveness of immunotherapy in pancreatic ductal adenocarcinoma (PDA) and explores potential synergistic effects with anti-PD-L1 immunotherapy. Using an autochthonous PDA model, the researchers found that while PDA-bearing mice had cancer cell-specific FAP+ cells, they did not respond to anti-CTLA-4 and anti-PD-L1 immunotherapy, similar to human PDA patients. Depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP) allowed immune control of tumor growth and revealed the efficacy of these immunotherapeutic antibodies. The FAP+ CAFs were the primary source of CXCL12, a chemokine that excluded T cells from regions containing cancer cells. Inhibiting CXCL12 receptor CXCR4 with AMD3100 synergized with anti-PD-L1 to significantly reduce cancer cell numbers, leading to a residual tumor composed only of premalignant epithelial cells and inflammatory cells. This study highlights the role of CXCL12 in tumor immune evasion and suggests that targeting CXCL12 from FAP+ CAFs may enhance the effectiveness of immunotherapy in PDA.The study investigates the mechanisms behind the ineffectiveness of immunotherapy in pancreatic ductal adenocarcinoma (PDA) and explores potential synergistic effects with anti-PD-L1 immunotherapy. Using an autochthonous PDA model, the researchers found that while PDA-bearing mice had cancer cell-specific FAP+ cells, they did not respond to anti-CTLA-4 and anti-PD-L1 immunotherapy, similar to human PDA patients. Depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP) allowed immune control of tumor growth and revealed the efficacy of these immunotherapeutic antibodies. The FAP+ CAFs were the primary source of CXCL12, a chemokine that excluded T cells from regions containing cancer cells. Inhibiting CXCL12 receptor CXCR4 with AMD3100 synergized with anti-PD-L1 to significantly reduce cancer cell numbers, leading to a residual tumor composed only of premalignant epithelial cells and inflammatory cells. This study highlights the role of CXCL12 in tumor immune evasion and suggests that targeting CXCL12 from FAP+ CAFs may enhance the effectiveness of immunotherapy in PDA.