Mendelian randomization reveals contrasting effects of immune signaling molecules on bone and articular cartilage malignancies.

BACKGROUND: The complex relationship between immune signaling molecules and cancer development remains incompletely understood. This study aimed to investigate potential causal relationships between specific immune factors and cancer risk via genetic instruments to overcome the limitations of traditional observational approaches. METHODS: Our study employed Mendelian randomization (MR) analyses using genetic variants as instrumental variables for immune signaling molecules. Multiple analytical approaches, such as the inverse-variance weighted method, MR‒Egger regression, weighted median, and simple median, were applied to evaluate causal relationships. Forest plots, scatter plots, and funnel plots facilitated comprehensive assessment, whereas circular dendrogram visualization provided broader immune pathway context. RESULTS: Our study revealed significant bidirectional effects of immune signaling on cancer risk. Three immune factors demonstrated protective associations: C-C motif chemokine 4 (OR: 0.682, 95% CI: 0.509–0.915, p = 0.011), leukemia inhibitory factor receptor (OR: 0.588, 95% CI: 0.374–0.924, p = 0.021), and macrophage inflammatory protein (OR: 0.521, 95% CI: 0.345–0.786, p = 0.002). In contrast, C-X-C motif chemokine 6 exhibited risk-increasing effects (OR: 1.380, 95% CI: 1.014–1.878, p = 0.040). These findings were consistent across multiple analytical approaches and cancer types, including cervical cancer and bone/articular cartilage malignancies. CONCLUSION: This study provides genetic evidence supporting the causal impact of specific immune signaling molecules on cancer development, with different chemokines and inflammatory factors exerting opposing influences on disease susceptibility.