Authors
Lizhong Yao, Baolong Li, Luke Zhang, Xueliang Zhou, Junyi Hou, Xiongyan Wu, Sheng Lu, Yifan Lu, Ruoyun Zhou, Zhenjia Yu, Zhijian Jin, Huan Zhang, Beiqin Yu, Zhenggang Zhu, Bingya Liu, Jing Sun, Jinping Zhang, Xiaofeng Xue, Jerrold R Turner, Chao Yan, Liping Su
Published in
Cancer research. Oct 09, 2026. Epub Oct 09, 2026.
Abstract
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.
PMID:
42853033
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.
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