INSR Armoring Protects CAR-NK and CAR-T Cells Against Tumor Stroma-Induced CAR Shedding by Maintaining Cholesterol Homeostasis
While chimeric antigen receptor (CAR)-engineered T and NK cell therapies have revolutionized hematological malignancy treatment, translating this success to solid tumors remains a persistent challenge. Here, we demonstrated a stromal-associated metabolic mechanism in which cancer-associated fibroblasts (CAFs) and macrophage-associated populations in gastrointestinal cancers contribute to CAR loss through CYP27A1-derived 27-hydroxycholesterol (27HC). 27HC triggered membrane cholesterol depletion, destabilizing lipid rafts and promoting the release of full-length CAR in ARF6+CD81+ microvesicle-enriched fractions. NK92 cells chronically exposed to sublethal 27HC adapted to this stress via an AKT-FOXO1-insulin receptor (INSR) signaling cascade that restores cholesterol biosynthesis. Capitalizing on this mechanism, "metabolically armored" INSR-overexpressing CAR-NK92 and primary CAR-T cells were engineered, which stabilized lipid rafts, preserved CAR expression, and improved antitumor activity in patient-derived organoids, precision-cut tumor slices, and xenografts. Collectively, these findings identify a stromal-mediated metabolic immune evasion pathway in gastrointestinal tumors, uncovering a potential strategy to potentiate CAR-engineered therapies.
Authors
- Beiqin Yu (ORCID: https://orcid.org/0000-0003-1043-0445)
- Sheng Lu (ORCID: https://orcid.org/0000-0003-4637-4588)
- Luke Zhang
- Xiaofeng Xue (ORCID: https://orcid.org/0000-0002-0963-7994)
- Zhenggang Zhu (ORCID: https://orcid.org/0000-0002-4800-8082)
- Zhijian Jin (ORCID: https://orcid.org/0000-0002-0370-3698)
- Jerrold R. Turner (ORCID: https://orcid.org/0000-0003-0627-9455)
- Bingya Liu (ORCID: https://orcid.org/0000-0002-4406-3762)
- Liping Su (ORCID: https://orcid.org/0000-0003-2401-0265)
- Bao‐Long Li (ORCID: https://orcid.org/0000-0003-1510-0162)
- Ruoyun Zhou
- Huan Zhang (ORCID: https://orcid.org/0000-0002-9838-0624)
- Jinping Zhang (ORCID: https://orcid.org/0000-0001-5537-5131)
- Xiongyan Wu (ORCID: https://orcid.org/0009-0004-1605-0034)
- Jing Sun (ORCID: https://orcid.org/0000-0001-9397-3511)
- Junyi Hou (ORCID: https://orcid.org/0000-0002-6343-7483)
- Lizhong Yao (ORCID: https://orcid.org/0009-0008-9477-6139)
- Zhenjia Yu (ORCID: https://orcid.org/0000-0002-3270-6855)
- Yifan Lu (ORCID: https://orcid.org/0009-0009-1728-3936)
- Chao Yan (ORCID: https://orcid.org/0009-0006-7288-9824)
- Jing Sun (ORCID: https://orcid.org/0009-0002-2446-9498)
Institutions
- Brigham and Women's Hospital (US)
- Ruijin Hospital (CN)
- Soochow University (CN)
- First Affiliated Hospital of Soochow University (CN)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-10-09
- DOI
- https://doi.org/10.1158/0008-5472.can-26-1047
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00