The vitamin D₃ axis in laryngeal cancer: a double-edged sword modulated by estrogen signaling

Laryngeal cancer remains a formidable clinical challenge, with growing evidence that vitamin D₃ acts as a potential therapeutic modulator. However, its precise role is complex, largely due to poor understanding of the mechanisms underlying its variable efficacy. This review synthesizes current knowledge to establish a comprehensive framework for vitamin D₃'s dichotomous role in laryngeal carcinogenesis. First, we clarify its two distinct mechanisms of action: (i) directly inhibiting laryngeal cancer cell proliferation and survival via the canonical vitamin D receptor (VDR) axis-triggering G₀/G₁ cell cycle arrest, inducing apoptosis, and reversing epithelial-mesenchymal transition (EMT); (ii) indirectly exerting anti-tumor effects by reprogramming the tumor immune microenvironment, including enhancing cytotoxicity of CD8⁺ T and natural killer (NK) cells, promoting dendritic cell maturation, and suppressing key inflammatory pathways such as the COX-2/PGE₂ axis. Subsequently, we propose that the net effect of vitamin D₃ signaling is context-dependent and double-edged, determined mainly by host-intrinsic and viral factors-most notably estrogen receptor α (ERα66) expression. Specifically, vitamin D₃-related products promote cell growth in ERα66-positive laryngeal cancer cell lines, but suppress growth in ERα66-negative lines, thereby aiding cancer therapy. This integration provides a nuanced paradigm, highlighting the need for biomarker-driven patient stratification to harness vitamin D₃'s therapeutic potential in laryngeal cancer.