Association of Macrophage Migration Inhibitory Factor (MIF) with Therapy Response and Clinical Outcomes in HPV-Related Head and Neck Squamous Cell Carcinoma: A Retrospective Longitudinal Analysis

Background: Macrophage migration inhibitory factor (MIF) shapes the tumor immune microen-vironment and has been implicated in head and neck squamous cell carcinoma (HNSCC), but its behavior may differ by HPV status. We evaluated whether dynamic changes in circulating MIF (ΔMIF) track disease severity and treatment response in HPV-positive (+) versus HPV-negative (-) HNSCC. Methods: In this single-center cohort study (n=27, 96 serial serum samples), clinical data were collected from diagnosis through therapy, remission, and relapse. MIF was quantified by ELISA and HPV status was assigned using p16 IHC, HPV DNA, and/or anti-E7 IgG. Associations with stage, treatment. and outcomes were analyzed using non-parametric/Fisher’s exact tests where appropriate. Results: At baseline (all patients), MIF did not correlate with clinical stage (p=0.63). Stratified analyses revealed heterogeneity: in HPV(+) patients (n=18 analyzable), 56% showed a direct cor-relation between high MIF levels and advanced stage disease, whereas HPV(−) patients (n=5) largely did not. Following concurrent cisplatin/radiation, HPV(−) patients demonstrated a consistent post-treatment decline in MIF (mean ΔMIF −1.23; p=0.031) and all achieved “no evidence of disease” status without recurrence. In contrast, HPV(+) patients showed mixed post-treatment MIF trajec-tories (mean ΔMIF +0.21; p=0.94). Over the full disease course, ΔMIF differed by HPV status (HPV(+) mean of +0.06 vs HPV(-) mean of −1.62; p=0.009. Conclusions: In HPV(-) HNSCC, post-treatment MIF decline strongly associates with effective response and remission, supporting MIF as a therapy-monitoring biomarker. In HPV(+) disease, baseline MIF may reflect severity, but post-treatment trajectories are heterogeneous and can decrease during active disease/relapse.