Abstract
<title>Abstract</title> <p>Canine transmissible venereal tumor (CTVT) displays a triphasic progression consisting of progressive (P), stationary (S), and regressive (R) phases, though the molecular mechanisms governing phase transitions remain incompletely understood. Recent evidence demonstrates differential activation of the TLR4/NF-κB/TNF-α pathway between P and S phases, with increased inflammatory cytokines and proapoptotic markers during stabilization—an apparent paradox given NF-κB's classical association with tumor promotion. In this review, we critically examine the evidence linking TLR4/NF-κB activation to CTVT stabilization and propose that this paradox arises from context-dependent reprogramming of NF-κB signaling within the unique allogeneic tumor microenvironment. We argue that immune recognition triggers inflammatory activation that overrides NF-κB-mediated survival signaling through suppression of Bcl-2 and recruitment of effector immune cells. We further identify major gaps in the literature, including the absence of functional causality studies, lack of longitudinal phase-specific analyses, and limited characterization of the R phase. We propose experimental strategies to address these limitations, including in vitro TLR4 stimulation assays, epigenetic profiling, and in vivo xenograft models. CTVT represents an invaluable natural model for investigating the transition from immune-evasive to immune-activated tumor states and may provide insights for immunotherapeutic development in comparative oncology.</p>