Abstract
<title>Abstract</title> <p> <bold>Background:</bold> Neoadjuvant immunochemotherapy (nCIT) is used for locally advanced oropharyngeal and hypopharyngeal squamous cell carcinoma (LA OPSCC), but the biological basis of pathological complete response (PCR) remains unclear. Metabolic reprogramming beyond immune activation may play a critical role. <bold>Methods:</bold> Serum metabolic profiles (iron, ferritin, lipids) from 116 LA OPSCC patients receiving nCIT were analyzed, and quantitative MRI assessed treatment-induced damage. Multi-omics sequencing was performed on pre-/post-treatment samples from 23 patients (10 PCR, 13 non-PCR). Immunofluorescence validated selected markers. <bold>Results:</bold> Post-treatment serum iron and triglycerides were significantly elevated in PCR patients (p=0.0252 and p=0.013) only in primary tumors, not lymph nodes. MRI showed increased T1 and T2* values selectively in primary tumors of PCR patients (p=0.017, p=0.015), correlating with serum markers. Metabolomics and transcriptomics identified significant lipid metabolism enzyme regulation. Targeted lipidomics revealed upregulation of plasmalogen PE, phosphatidylserine, and phosphatidylcholine in PCR tumors. Proteomics showed SELENOI (involved in PE-P synthesis) upregulated in PCR patients, with strong positive correlation with TFRC (rho=0.951, p<0.0001). Immunofluorescence confirmed elevated SELENOI, TFRC, 4-HNE, and ferritin in PCR tumors, along with increased malondialdehyde and lipid ROS, consistent with ferroptosis. <bold>Conclusions:</bold> Integrated multi-omics reveals that PCR following nCIT is associated with a coordinated lipid remodeling signature involving SELENOI-associated PE-P enrichment and TFRC-associated iron availability, suggesting a dual priming state for ferroptosis. These findings identify candidate biomarkers for further validation. </p>