Tumor cell-intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers but has shown limited efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). The cellular and molecular factors that influence CAR T cell therapy response remain largely unknown. By integrating modular in vivo CRISPR screens with single-cell genomics and immunocompetent orthotopic models of PDAC, we uncover oxidative and proteotoxic stress pathways as previously unknown modulators of CAR T cell therapy response. Disruption of stress regulatory genes, particularly Keap1 and Slc33a1, sensitizes PDAC tumors to CAR T cell killing in vivo. Hyperactivation of the Nrf2 pathway by genetic ablation of Keap1 or endogenous engineering of clinically observed Keap1 or Nfe2l2 mutations enhances tumor susceptibility to CAR T cell therapy. Thus, tumor-intrinsic molecular stress phenotypes can induce unexpected cell state-specific vulnerabilities to cell-based immunotherapies. These findings provide a foundation to improve efficacy of CAR T cell therapy in solid malignancies and to better stratify patients with cancer by tumor genotype.