2. Academic Validation
  3. Targeting IGF1R Overcomes Armored and Cold Tumor Microenvironment and Boosts Immune Checkpoint Blockade in Triple-Negative Breast Cancer

Targeting IGF1R Overcomes Armored and Cold Tumor Microenvironment and Boosts Immune Checkpoint Blockade in Triple-Negative Breast Cancer

  • Adv Sci (Weinh). 2025 Jul 18:e01341. doi: 10.1002/advs.202501341.
Mengyun Wan 1,  Jie Mei 2,  Yun Cai 3,  Ji Zhou 1,  Ningyi Xue 2,  Ying Jiang 4,  Yan Zhang 4 5,  Jingjing Huang 6,  Yichao Zhu 1 7
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
  • 2 The First Clinical Medicine College, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 3 Department of Central Laboratory, The First People's Hospital of Jintan, Jintan Affiliated Hospital of Jiangsu University, Changzhou, Jiangsu, 213251, China.
  • 4 Departments of Gynecology, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, Jiangsu, 214023, China.
  • 5 Departments of Gynecology, Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
  • 6 Department of Geriatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 211800, China.
  • 7 Department of General Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, 214504, China.
PMID: 40679093 DOI: 10.1002/advs.202501341
Abstract

In the previous study, patients with tumors based on Collagen deposition and immunoreactivity are classified and identified the armored & cold subtype as the most treatment-refractory tumor type. Triple-negative breast Cancer (TNBC) is the most lethal tumor type globally, making it critical to overcome the armored and cold tumor microenvironment (TME) for effective treatment of these patients. In this study, the transcriptomic Collagen activity and immune profiles of Cancer patients treated with immune checkpoint blockade (ICB) are analyzed, and found that intratumoral Collagen is associated with an unfavorable immunotherapeutic response and T cell exhaustion. Additionally, Collagen is shown to regulate IGF1R expression at both transcriptional and post-translational levels via SOX4 and DDR1, respectively. It is also found that IGF1R promotes tumor cell migration and invasion, as well as T cell exhaustion, with these effects mediated through Collagen. Moreover, in vivo inhibition of IGF1R reversed the armored & cold TME, thereby enhancing anti-PD-1 therapy. In conclusion, this study identified IGF1R as a novel therapeutic target for the immuno-collagenic subtype, and combining IGF1R inhibition with anti-PD-1 therapy provides a promising foundation for a novel combination immunotherapy regimen for TNBC.

Keywords

ICB; IGF1R; TNBC; armored & cold tumors; collagen; tumor microenvironment.

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