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A Neuron Projection Guidance Signature Associates with Immune-Cold Tumor Microenvironment and Poor Outcomes in Breast
Kei Kawashima1,2, Kohei Chida1, Masanori Oshi2
1Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Annals of Surgical Oncology
|July 25, 2026
Summary
Nerve recruitment activity in breast cancer, particularly triple-negative breast cancer (TNBC), is linked to an immune-cold tumor microenvironment (TME), reduced chemotherapy response, and poorer survival outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Neuroscience
Background:
- Neural involvement in the tumor microenvironment (TME) influences cancer aggressiveness.
- Characterizing neural TME in breast cancer is challenging due to low nerve density.
- This study explores cancer-mediated nerve recruitment in breast cancer TME.
Purpose of the Study:
- Investigate the clinical relevance of nerve recruitment activity in breast cancer TME.
- Quantify nerve recruitment using a Neuron Projection Guidance (NPG) score.
- Analyze associations between NPG score and clinical outcomes.
Main Methods:
- Analyzed transcriptomic and clinical data from 9017 breast cancer patients.
- Utilized GSVA of a MSigDB gene set to generate NPG score for nerve recruitment.
- Dichotomized patients based on cohort-specific medians.
Main Results:
- NPG score correlated with axonogenesis genes and lower proliferation (e.g., Ki67).
- High NPG tumors showed lower mutational burden, neoantigen load, and immune infiltration (immune-cold TME).
- Higher NPG scores associated with poorer response to neoadjuvant chemotherapy and worse survival, especially in TNBC.
Conclusions:
- Identified novel tumor-neuronal cross-talk in TNBC biology.
- This cross-talk links to an immune-cold TME, reduced chemotherapy efficacy, and poor outcomes.
- Potential implications for risk stratification and treatment decisions in TNBC.
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