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  3. Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment

Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment

  • Research (Wash D C). 2025 Oct 9:8:0915. doi: 10.34133/research.0915.
Qianyu Wang 1 2,  Shasha Li 3,  Yuan Wu 1,  Xiankuo Yu 1,  Yifei Dai 4,  Yumei Wang 1,  Lu Li 2,  Ming Yang 4 5,  Kequan Lin 6 7,  Wei Shao 4 8,  Haiyan Wang 4 9,  Huili Wang 4,  Guanbin Zhang 10,  Dong Wang 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 2 School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China.
  • 4 Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 5 Department of Statistics and Data Science, Tsinghua University, Beijing 100084, China.
  • 6 Department of Cardiology of The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 7 Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou 310009, China.
  • 8 Chinese Institutes for Medical Research, Beijing 100069, China.
  • 9 Department of Pathology, School of Medicine, Qinghai University, Xining 810001, China.
  • 10 School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
PMID: 41079672 DOI: 10.34133/research.0915
Abstract

The infiltration of myeloid-derived suppressor cells (MDSCs) is critical for the establishment of immunosuppressive tumor microenvironment (TME), yet no approved therapies specifically block it. Here, we employed a gene signature-based drug screening approach to identify potential agents for reversing MDSC-mediated immunosuppression in triple-negative breast Cancer (TNBC). Transcriptomic analysis of 73,326 tumor samples and 190,588 single cells revealed C-X-C motif ligand 1 (CXCL1) and CXCL2 as the key gene signature of MDSC infiltration. Combining this gene signature with high-throughput sequencing-based high-throughput screening (HTS2), we identified ponatinib as a potential inhibitor of MDSC infiltration. By employing multiple preclinical models, we demonstrated that ponatinib blocks MDSC infiltration and reverses the immunosuppressive TME, thus inhibiting TNBC growth in a TME-dependent manner, and significantly enhances anti-programmed cell death-ligand 1 (PD-L1) immunotherapy efficacy. Mechanistically, ponatinib directly inhibits p38α kinase activity, reducing signal transducer and activator of transcription 1 (STAT1) phosphorylation at Ser727 and suppressing CXCL1 and CXCL2 expression in Cancer cells, thereby blocking MDSC infiltration. Our findings establish ponatinib as a novel inhibitor of MDSC-mediated immunosuppressive TME and underscore its therapeutic potential in combination with immune checkpoint blockade for TNBC treatment.

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