Abstract
T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti–programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.
Authors
Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li
Figure 7
High levels of IGF2 are positively correlated with an unfavorable prognosis and resistance to immunotherapy in patients with cancer.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)