Work

Spatial proteomic profiling reveals an association between NF1-Ras/Raf/MEK signaling and immune cell infiltration in locally advanced triple-negative breast cancer

Year: 2026

Type: article

Abstract: BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy characterized by significant molecular heterogeneity with a limited range of targeted therapy options. Better resolution of the spatial interactions between tumor cells and the immune microenvironment is essential for identifying actionable vulnerabilities. METHODS: Here we employed GeoMx Digital Spatial Profiling (DSP) to investigate the proteomic landscape of 72 immuno-oncology biomarkers in normal breast, primary breast cancer, and metastatic axillary lymph node tissues of treatment-naïve TNBC patients (n=29) who underwent upfront breast surgery. RESULTS: Through comprehensive profiling, we identified the tumor suppressor protein, neurofibromin (NF1), as one of the vulnerabilities in TNBC. Spatially resolved analysis revealed that NF1 downregulation is strongly associated with Ras/Raf/MEK pathway activation. This downregulation of NF1 level was characteristic of tumor regions with a high representation of tumor infiltrating lymphocytes (TILs). Furthermore, low NF1 levels significantly correlated with reduced disease-free survival, suggesting its potential clinical utility as a biomarker. We also observed a high degree of proteomic similarity between primary breast tumors and the matched lymph node metastases. CONCLUSIONS: These findings advance our understanding of TNBC spatial proteomic profiles and suggest that targeting the NF1-Ras/Raf/MEK axis may offer novel strategy for clinical management of TNBC patients with immune "hot" tumors.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2026.102934