Gallic acid chemoprevention of oral carcinogenesis is associated with HSD11β2 upregulation and immune remodeling.

Naturally derived phytochemicals such as gallic acid (GA) exhibit multitargeted anticancer properties and favorable safety profiles, yet the molecular mechanisms underlying their chemopreventive effects in head and neck squamous cell carcinoma (HNSCC) remain incompletely defined. Using a 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis mouse model, we evaluated GA's effects on tumor progression, immune modulation, and stress-hormone-related pathways. Phenotypic outcomes were assessed by histopathology, proliferation markers, and in vitro cytotoxicity assays. Transcriptomic changes were profiled by RNA sequencing, pathway enrichment and validation using RT-qPCR, Western blotting, ELISA, and flow cytometry. GA selectively inhibited proliferation of HNSCC cell lines (CAL27, SCC83) while sparing normal oral epithelial cells (TE1177). In vivo, GA reduced tumor burden and histopathologic severity without affecting body weight. RNA-seq analysis revealed coordinated modulation of immune and stress-response pathways, including upregulation of Carmil2, Cd27, and Cd209d and downregulation of Fos, Pappa, and Hif1a. GA increased HSD11β2 expression in vitro and in vivo and reduced cortisol in cAMP-stimulated HNSCC cells, findings consistent with reduced local glucocorticoid signaling. GA also increased IL-2 and decreased IL-10 in T cells, reduced monocytic MDSCs, and lowered PD-L1 on pro-inflammatory macrophages. Together, these findings identify HSD11β2/glucocorticoid metabolism as a potential axis associated with GA-mediated oral cancer chemoprevention.