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Peer-reviewedCC BYScience Advances

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

  • Julia Fröse1,2
  • Evelyn Chen1,2
  • Charles A. Whittaker1
  • Paul Leclerc1,2
  • Sean Doherty1,2
  • Adam Langenbucher1,2
  • Jasmine Shao1
  • Riley D. Hellinger1,2
  • Daniel Goulet1,2
  • Tuomas Tammela3,4
  • Francisco J. Sánchez-Rivera1,2
  • Michael T. Hemann1,2
4 affiliations
  1. 1The David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.
  2. 2Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  3. 3Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  4. 4David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{frose2026tumor,
  title = {{Tumor cell–intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer}},
  author = {Julia Fröse and Evelyn Chen and Charles A. Whittaker and Paul Leclerc and Sean Doherty and Adam Langenbucher and Jasmine Shao and Riley D. Hellinger and Daniel Goulet and Tuomas Tammela and Francisco J. Sánchez-Rivera and Michael T. Hemann},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh8973},
  url = {https://www.science.org/doi/10.1126/sciadv.aeh8973},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tumor cell–intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer
AU  - Julia Fröse
AU  - Evelyn Chen
AU  - Charles A. Whittaker
AU  - Paul Leclerc
AU  - Sean Doherty
AU  - Adam Langenbucher
AU  - Jasmine Shao
AU  - Riley D. Hellinger
AU  - Daniel Goulet
AU  - Tuomas Tammela
AU  - Francisco J. Sánchez-Rivera
AU  - Michael T. Hemann
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aeh8973
UR  - https://www.science.org/doi/10.1126/sciadv.aeh8973
AB  - 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.
SN  - 2375-2548
ER  -