Background: Persistent HPV 16 expression and NF-κB activation drive inflammation and immune suppression in head and neck squamous cell carcinoma (HNSCC). APG-157 is a proprietary oral botanical immunomodulator with anti-inflammatory and tumor-microenvironment (TME) reprogramming activity. This Phase 2A clinical study evaluated its molecular and immunologic effects in patients with HNSCC. Methods: Fourteen patients received APG-157 (200 mg TID for 4 weeks) under IRB approval at VAGLAHS. Paired pre- and post-treatment saliva and tumor biopsies (n=24) were analyzed for HPV 16 E7 integration and expression by qPCR/RT-qPCR, and for expression of p16, NF-κB, gigaxonin, E-cadherin, and Snail by molecular and immunohistochemical assays. Paired PBMCs from 5 patients underwent single-cell RNA sequencing (scRNA-seq) to characterize systemic immune modulation. Results: PCR identified presence of HPV 16 E7 sequences in 2/7 OC and 4/7 OPC (total of 6/14) pre-APG-157 samples. Expression of p16 by IHC showed p16 positivity in 4/7 OC and 7/7 OPC samples. APG-157 treatment reduced HPV 16 E7 integration and expression levels in 4 of 6 HPV 16 E7 pre-APG-157 positive samples in the saliva and tumor, confirming a direct antiviral effect. NF-κB expression decreased concordantly, whereas gigaxonin (a cytoskeletal regulator linked to NF-κB degradation) increased, suggesting restoration of proteasomal regulation and suppression of inflammatory signaling. Expression of epithelial integrity markers (E-cadherin↑, Snail↓) improved, indicating a shift towards a less invasive phenotype. Notably, salivary HPV 16 detection correlated with tumor expression, validating saliva as a non-invasive biomarker for HPV-driven diseases. scRNA-seq of PBMCs revealed post-treatment expansion of activated B cells and effector T-cell clusters consistent with systemic immune activation. These findings indicate that APG-157 exerts coordinated local and systemic immunomodulatory effects by simultaneously suppressing oncogenic viral and inflammatory pathways and enhancing lymphocyte function. Conclusions: APG-157 demonstrates dual antiviral and immunoregulatory activity in HNSCC, suppressing HPV 16 and NF-κB while promoting immune activation and epithelial restoration. APG-157 uniquely enhances gigaxonin-mediated NF-κB regulation and downregulates HPV 16 E7 expression, defining a new therapeutic axis for oral immunomodulation. These data support the continued development of APG-157 as an oral immunotherapy for HPV-driven and immunologically “cold” head and neck cancers, both as a monotherapy and as a combinatorial agent with chemo-radiation or immune checkpoint inhibitors.