DataVXAdvanced SciencePaper
journal article·2026-07Open access

Tumor‐Intrinsic ARHGEF3 Enhances Antitumor Immunity by Promoting T‐Cell Infiltration and Limiting Myeloid Cell‐Mediated Immunosuppression

Yue Li, Lan Wang, Zihao Zhang, Chunmei Qian, Ning Li, Wei Huang, Qian Ba, Xiaojian Liu, Mayu Sun

Advanced Science· Volume 13· Issue 38
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Abstract

ABSTRACT A lack of effective antitumor T‐cell immunity often drives immune evasion and immunotherapy resistance. Here, we demonstrated that tumor‐intrinsic ARHGEF3 reprogrammed the tumor microenvironment into a T‐cell‐inflamed state, resulting in potent antitumor effects. Mechanistically, ARHGEF3 functioned as a guanine nucleotide exchange factor that activated the RHOA‐ROCK‐PTEN cascade and inhibited AKT signaling. This inhibition upregulated IRF1‐dependent chemokines CXCL10 and CXCL11 to drive T‐cell infiltration, while suppressing FASN‐mediated fatty acid synthesis to limit myeloid cell‐mediated immunosuppression. The dual effects elicited robust T‐cell immunity and overcame tumor resistance to immunotherapy. In human tumors, ARHGEF3 expression correlated positively with T‐cell‐inflamed signatures, improved clinical outcomes, and responsiveness to immunotherapy. Collectively, these findings identify ARHGEF3 as a key modulator linking chemokine signaling with lipid availability to shape T‐cell immunity, offering a promising therapeutic strategy to overcome immunotherapy resistance.
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Research context

OpenAlex topics: Immune cells in cancer · Cancer Immunotherapy and Biomarkers · Chemokine receptors and signaling

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Science and Technology Innovation Center Shanghai Municipal Hospital of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Shanghai China

The Third Affiliated Hospital of Beijing University of Chinese Medicine Beijing China

CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai China

Department of Pharmacy The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China

Institute of Image Processing and Pattern Recognition Key Laboratory of System Control and Information Processing Ministry of Education of China Shanghai Jiao Tong University Shanghai China

Funding

National Natural Science Foundation of China

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