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Background <p>Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined.</p> Methods <p>We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response.</p> Results <p>We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype—compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g., SCAN-B: HR = 4.7, <i>P</i> = 0.01) and TLR7score-low (HR = 3.37, <i>P</i> = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell–related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner.</p> Conclusions <p>Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.</p>

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TLR7 signature of tumour innervation reveals two distinct pathways of triple-negative breast cancer progression

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Dong-Yu Wang,
  • Zhe Jiang,
  • Yaacov Ben-David,
  • Susan J. Done,
  • Eldad Zacksenhaus

摘要

Background

Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined.

Methods

We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response.

Results

We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype—compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g., SCAN-B: HR = 4.7, P = 0.01) and TLR7score-low (HR = 3.37, P = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell–related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner.

Conclusions

Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.