Toll-like Receptor 3 as a Context-Dependent Molecular Switch in Epithelial Cancers: Balancing Cell Death and Tumor-Supportive Programs

Toll-like receptor 3 (TLR3) is a double-stranded RNA sensor that plays a dual and context-dependent role in epithelial cancers, promoting either regulated cell death (RCD) or tumor-supportive programs. While TLR3 activation has been widely explored for its capacity to induce apoptosis or necroptosis and enhance antitumor immunity, accumulating evidence indicates that cancer cells can use TLR3 signaling to sustain proliferation, migration, stemness, and therapy resistance. In this review, we provide a comprehensive and mechanistic analysis of TLR3 signaling in epithelial cancers, encompassing canonical and non-canonical modules that regulate cancer cell fate. We examine how TLR3 activation engages interconnected RCD programs, including apoptosis, necroptosis, and immunogenic cell death, and contrast these with pathways driving tumor plasticity and progression. Importantly, we discuss the key determinants governing TLR3 signaling output, including signaling complex composition; ligand origin and delivery; TLR3 subcellular localization; and cancer cell-intrinsic factors such as genetic, epigenetic, and metabolic states. We propose an integrative framework in which TLR3 signaling influences cancer cell fate according to cellular and microenvironmental context.