Advanced Science | IGF1R Regulates Collagen Microenvironment to Enhance Immunotherapy in Triple-Negative Breast Cancer

This study reveals the critical role of IGF1R in collagen-mediated immune suppression in triple-negative breast cancer and identifies that targeting IGF1R can effectively reverse the 'armored and cold tumor microenvironment', enhancing anti-PD-1 therapy efficacy. The research provides a novel strategy for combination immunotherapy in triple-negative breast cancer.

 

Literature Overview
The article 'Targeting IGF1R Overcomes Armored and Cold Tumor Microenvironment and Boosts Immune Checkpoint Blockade in Triple-Negative Breast Cancer', published in Advanced Science, reviews collagen deposition and its impact on immune activity in triple-negative breast cancer, identifying IGF1R as a key therapeutic target for this subtype.

Background Knowledge
Triple-negative breast cancer (TNBC) is the most aggressive and challenging breast cancer subtype, lacking effective targeted therapies. Tumor microenvironment (TME) characteristics, such as immune cell infiltration and extracellular matrix (ECM) density, significantly influence immunotherapy responses. Building upon the previously established 'armored and cold tumor' subtypes, this study explores collagen-regulated molecular mechanisms and their impact on immune checkpoint blockade (ICB). Research shows collagen upregulates IGF1R expression through transcription factor SOX4 and collagen receptor DDR1, subsequently promoting tumor invasion and suppressing T-cell function. In vivo inhibition of IGF1R remodels TME into a 'soft and hot' phenotype, significantly enhancing anti-PD-1 therapeutic outcomes. These findings provide theoretical foundations and clinical translation potential for precision immunotherapy in TNBC.

 

 

Research Methods and Experiments
The research team first analyzed the correlation between collagen deposition and immune scores in TNBC patient cohorts, revealing significantly elevated collagen levels and reduced immune cell infiltration in non-responders. Venn analysis screened collagen-associated genes overexpressed in non-responders, ultimately identifying IGF1R as a key candidate. Further experiments demonstrated collagen-induced IGF1R upregulation, regulated by transcription factor SOX4 and receptor DDR1 at transcriptional and post-translational levels, respectively. Functional validation included gene knockdown and small-molecule inhibitor PPP interventions to assess IGF1R's role in tumor migration, invasion, and T-cell exhaustion.

Key Conclusions and Perspectives

• Collagen deposition exhibits significant negative correlation with immune scores, where high collagen levels reduce T-cell infiltration and increase exhaustion, lowering immunotherapy response rates
• IGF1R is overexpressed in armored and cold TME subtypes, with collagen upregulating IGF1R through SOX4 at transcriptional level and DDR1 at post-translational level
• IGF1R inhibition effectively reverses collagen-mediated TME immunosuppression, enhancing anti-PD-1 therapeutic efficacy
• IGF1R promotes collagen secretion and migration in cancer-associated fibroblasts (CAFs), suggesting dual inhibition of tumor and stromal remodeling through IGF1R targeting

Research Significance and Prospects
This study provides new biomarkers and therapeutic strategies for TNBC immunotherapy, establishing IGF1R as a potential predictive marker and therapeutic target. Future research should explore combination efficacy of IGF1R inhibitors with diverse ICB regimens and evaluate their applicability in other collagen-high tumor types.

 

 

Conclusion
This study systematically elucidates the mechanism by which collagen regulates the TNBC immune microenvironment through the IGF1R-SOX4/DDR1 axis, proposing that targeting IGF1R effectively overcomes armored and cold TME barriers to enhance anti-PD-1 therapy. The findings not only offer new therapeutic targets for TNBC patients but also establish theoretical foundations for immunotherapy strategies in other collagen-high tumors, demonstrating significant translational potential.

 

Mengyun Wan, Jie Mei, Yun Cai, Jingjing Huang, and Yichao Zhu. Targeting IGF1R Overcomes Armored and Cold Tumor Microenvironment and Boosts Immune Checkpoint Blockade in Triple‐Negative Breast Cancer. Advanced Science.