Combining Mendelian randomization and multiomics data to determine the causal relationship between systemic inflammation and head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, is strongly associated with chronic inflammation. While chronic inflammation is often localized, systemic inflammation represents a generalized, systemic state of immune activation characterized by elevated circulating cytokines and changes in immune cell populations. However, the causal relationship between systemic inflammation and HNSCC remains elusive. This study employed Mendelian randomization (MR) to address this knowledge gap, using genetic variants as instrumental variables to estimate potential causal effects, thus minimizing confounding and reverse causation. We applied two-sample Mendelian randomization (TSMR) and two-step mediation analyses to explore the potential causal relationships between HNSCC, circulating immune cell phenotypes, and inflammatory proteins. Potential confounders were assessed using the Open Targets Genetics platform, and sensitivity analyses were performed to ensure the robustness of our findings. The MR results were further assessed using transcriptomic and proteomic datasets. TSMR revealed CXCL11, CD40, and interleukin-10 receptor subunit beta (IL10RB) as potential protective factors against HNSCC, whereas cystatin D (CST5) was associated with increased susceptibility. HNSCC is causally associated with multiple immune phenotypes, including T cells, B cells, natural killer (NK) cells, dendritic cells, and regulatory T cells (Tregs). Mediation analyses revealed several key mediators that may influence inflammatory pathways. Data from transcriptomic and proteomic cohorts supported significant expression changes in these genes and proteins, which correlated with patient prognosis. Furthermore, single-cell RNA sequencing revealed CXCL-mediated monocyte-T-cell interactions, elevated Treg populations, and altered expression of the CXCL11 receptor. This study suggests a bidirectional causal relationship between systemic inflammation and HNSCC, with CXCL11 and specific immune cell phenotypes serving as central mediators. These findings provide mechanistic insights into the HNSCC immunoinflammatory network and highlight potential biomarkers for early detection and targets for immunotherapeutic intervention.