A study shows that targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts (CAFs) enhances the effectiveness of anti-PD-L1 immunotherapy in pancreatic cancer. In an autochthonous model of pancreatic ductal adenocarcinoma (PDA), mice with PDA had cancer-specific CD8+ T cells but did not respond to anti-CTLA-4 or anti-PD-L1 therapies. However, depleting FAP+ CAFs allowed immune control of tumor growth and revealed the efficacy of these therapies. FAP+ CAFs are the primary source of CXCL12, a chemokine that suppresses T-cell activity and promotes tumor immune evasion. Inhibiting CXCR4, the receptor for CXCL12, with AMD3100 synergized with anti-PD-L1 to significantly reduce cancer cells, as evidenced by loss of heterozygosity of the Trp53 gene. The residual tumor consisted of premalignant epithelial cells and inflammatory cells. These findings suggest that CXCL12 from FAP+ CAFs is a key driver of immune evasion in PDA. The study highlights the importance of targeting stromal cells and chemokine pathways to improve immunotherapy outcomes in pancreatic cancer. The results may have broad clinical relevance, as FAP+ cells are present in most human adenocarcinomas. The study also underscores the value of using genetically engineered models to understand tumor immune evasion mechanisms.A study shows that targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts (CAFs) enhances the effectiveness of anti-PD-L1 immunotherapy in pancreatic cancer. In an autochthonous model of pancreatic ductal adenocarcinoma (PDA), mice with PDA had cancer-specific CD8+ T cells but did not respond to anti-CTLA-4 or anti-PD-L1 therapies. However, depleting FAP+ CAFs allowed immune control of tumor growth and revealed the efficacy of these therapies. FAP+ CAFs are the primary source of CXCL12, a chemokine that suppresses T-cell activity and promotes tumor immune evasion. Inhibiting CXCR4, the receptor for CXCL12, with AMD3100 synergized with anti-PD-L1 to significantly reduce cancer cells, as evidenced by loss of heterozygosity of the Trp53 gene. The residual tumor consisted of premalignant epithelial cells and inflammatory cells. These findings suggest that CXCL12 from FAP+ CAFs is a key driver of immune evasion in PDA. The study highlights the importance of targeting stromal cells and chemokine pathways to improve immunotherapy outcomes in pancreatic cancer. The results may have broad clinical relevance, as FAP+ cells are present in most human adenocarcinomas. The study also underscores the value of using genetically engineered models to understand tumor immune evasion mechanisms.