The emerging importance of TNF-α in canine mammary cancer: A narrative overview

Chronic inflammation is a key driver of tumour initiation and progression and tumour necrosis factor-alpha (TNF-α) is one of the central cytokines linking inflammatory signalling with cancer aggressiveness in canine mammary tumours (CMTs). Within the tumour microenvironment (TME)-comprising tumour cells, stromal cells, immune infiltrates and extracellular matrix-TNF-α regulates pathways involved in proliferation, survival, angiogenesis, metastasis and immune evasion, primarily via activation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Elevated TNF-α expression in CMTs correlates with inflammatory cell infiltration, dysregulated microRNAs such as miR-21 and miR-146b, increased High mobility group box 1 (HMGB1) release and tumour-promoting inflammatory feedback loops. Conversely, TNF-α also displays context-dependent antitumour properties, including the induction of apoptosis, pyroptosis and vascular disruption, as demonstrated by oncolytic Newcastle disease virus and combination therapies. High TNF-α levels in plasma and tumour tissue serve as biomarkers of malignancy, tumour grade and clinical outcome in dogs. Collectively, the multifaceted role of TNF-α in CMT pathophysiology highlights its significance as both a driver of disease progression and a potential therapeutic target, underscoring the need for carefully modulated TNF-α-based immunotherapeutic approaches in canine mammary cancer.