Unveiling the genetic role of skin-gut microbial axis in pan-cancer development.

e22503 Background: The skin and gut are critical, microbe-rich barriers whose dynamic interplay modulates immune homeostasis and disease susceptibility. Although the gut-skin axis has been well-established in the context of inflammatory bowel diseases, how skin microbial communities shape gut microbial composition and, in turn, influence cancer development remains insufficiently characterized. Methods: We leveraged large-scale genome-wide association (GWAS) data from the skin microbiome dataset, the MiBioGen consortium, and the IEU Open GWAS database to systematically dissect potential causal relationships among 147 skin microbial taxa, 196 gut microbial taxa, and 27 distinct cancer types. Genetic variants with p < 1 × 10⁻⁵ were selected as instrumental variables (IVs). Sensitivity analyses were conducted to ensure the robustness of results, and mediation analysis was applied to assess the role of the skin-gut axis during oncogenesis. Results: Using a bidirectional genetic approach, we identified 14557 IVs for microbial traits, establishing 11,998 significant “skin-to-gut” and 2,559 “gut-to-skin” links. These findings reveal a robust skin–gut microbial axis associated with pan-cancers. A total of 164 “skin-to-cancer” and 211 “gut-to-cancer” associations were unveiled, elucidating the causal effects of skin and gut microbiota on cancer. Notably, Streptococcus salivarius (ASV022_Moist) showed divergent effects on pancreatic (β = 0.102, p = 3.45 × 10⁻²) and endometrial cancers (β = -4.41 × 10⁻⁴, p = 2.91 × 10⁻²), underscoring the complexity of microbial influences across tumors. Mediation analyses further identified 65 significant “skin–gut–cancer” pathways, suggesting that certain taxa operate both as exposures and mediators in oncogenic processes. Together, these results provide genetic evidence that the skin–gut microbial axis constitutes a previously underappreciated determinant of cancer risk. By pinpointing key microbial taxa and bidirectional interactions, our study highlights the potential of targeting both skin and gut microbiota in future cancer prevention and therapeutic strategies. Conclusions: This study provides robust genetic evidence supporting a skin-gut axis influencing cancer risk via complex microbial interactions, underscoring the translational potential of targeting both skin and gut microbiota as a novel therapeutic approach for cancer prevention and treatment, emphasizing the translational relevance of these microbial networks in oncology.