ArticleThe Journal of clinical investigation2024
Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
- Pan-tumor spatial transcriptomics reveals conserved properties of tumor organization.Cell reports. Medicine · 2026Article
- Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.Molecular cancer · 2026Review
- Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8Science advances · 2026Article
- GALNT5 drives colorectal cancer progression and chemoresistance via PI3K/Akt/ABCC1 axis.Journal of cancer research and clinical oncology · 2026Article
- Potential of RAD51C as a hub gene and therapeutic target in bladder cancer: insights from bioinformatics and experimental analysis.International journal of surgery (London, England) · 2026Article
- HBx-Associated Reactivation of the IGF2 Locus in Chronic HBV Infection and HBV-Related Hepatocarcinogenesis: Evidence Boundaries and Biomarker Implications.Biomedicines · 2026Review
- Virtual screening and experimental validation of small-molecule compounds targeting AR in prostate cancer.Molecular diversity · 2026Article
- Bidirectional crosstalk between cancer-associated fibroblasts and tumor immunity: shaping the microenvironment and response to immune checkpoint therapy.Experimental hematology & oncology · 2026Review
- Review
- IGFBP in tumor immunity: a novel target for cancer immunotherapy.Journal of translational medicine · 2026Review
- The IGF signaling axis in thyroid cancer: biological complexity and therapeutic challenges.Endocrine connections · 2026Review
- Bidirectional Interactions Between Immune Regulation and the Insulin-like Growth Factor Axis in Colorectal Cancer.International journal of molecular sciences · 2026Review
- Cancer-Associated Fibroblasts Functions as Multifunctional Architects of the Tumor Stroma and Represent Emerging Therapeutic Vulnerabilities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Unleashing lncRNA THOR: roles in cancer progression and clinical outlook.Molecular genetics and genomics : MGG · 2026Review
- Immunotherapy for patients with EGFR-TKI-resistant non-small-cell lung cancer: Potential mechanisms, efficacy predictors, and therapeutic integration.Chinese medical journal pulmonary and critical care medicine · 2026Review
- Review
- The Spatiotemporal Heterogeneity of Tumor-Associated Stromal Cells: Reprogramming Plasticity to Unlock Precision Cancer Immunotherapy.Cancer communications (London, England) · 2026Review
- Article
- Formation and remodeling of immunological niches in solid tumors: organ-specific architectures, inflammatory parallels, and therapeutic reprogramming.Frontiers in immunology · 2026Review
- Dual Graphene Oxide-Based Multigene Delivery for Cancer Elimination via Stromal and Immune Reprogramming.International journal of biomaterials · 2026Article
Corrections and comments
- Erratum issued
Authors and funding
23 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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