Background: Merkel cell polyomavirus (MCPyV) has been established as an etiological agent in Merkel cell carcinoma (MCC), yet its role in other cutaneous neoplasms remains under investigation. The impact of the host’s immunogenetic characteristics on the persistence of Merkel cell polyomavirus (MCPyV) in non-melanoma skin cancer (NMSC) is not yet well understood. Objective: Our aim was to investigate the presence of MCPyV in various skin lesions, particularly NMSC, and its association with cytokine gene polymorphisms related to immune regulation. Methods: We analyzed 274 skin biopsies (lesional, perilesional, and healthy skin) from 84 patients undergoing dermatological evaluation. MCPyV DNA and polymorphisms in IL-6, IL-10, IFN-γ, and TNF-α genes were detected using PCR-based assays. Results: MCPyV was significantly more prevalent in NMSC and non-cancerous lesions than in surgical margins or healthy skin (p = 0.050 and 0.048, respectively). Concordance between lesion and margin samples was low (κ = 0.305), suggesting microenvironment-specific viral persistence. Notably, high-expression IL-10 genotypes (-1082 GG) and low-expression IL-6 genotypes (-174 AA) were significantly associated with MCPyV detection (p = 0.048 and p = 0.015, respectively). Conclusions: MCPyV preferentially localizes to NMSC lesions, particularly in individuals with immunogenetic profiles favoring viral persistence. Since the role of MCPyV in the pathogenesis of NMSC remains uncertain, our results highlight the need for further studies to clarify whether the lesion’s microenvironment supports viral persistence or indicates a more intricate interaction between the virus and the host, which could be significant for the development of skin cancer.

Background: Merkel cell polyomavirus (MCPyV) has been established as an etiological agent in Merkel cell carcinoma (MCC), yet its role in other cutaneous neoplasms re-mains under investigation. In the context of non-melanoma skin cancer (NMSC), the influence of host immunogenetics on MCPyV persistence is poorly understood. Objec-tive: To investigate the presence of MCPyV in various skin lesions, particularly NMSC, and its association with cytokine gene polymorphisms related to immune regulation. Methods: We analyzed 274 skin biopsies (lesional, perilesional, and healthy skin) from 84 patients undergoing dermatological evaluation. MCPyV DNA and polymorphisms in IL-6, IL-10, IFN-γ, and TNF-α genes were detected using PCR-based assays. Results: MCPyV was significantly more prevalent in NMSC and non-malignant lesions than in surgical margins or healthy skin (p = 0.050 and 0.048, respectively). Concordance be-tween lesion and margin samples was low (κ = 0.305), suggesting microenviron-ment-specific viral persistence. Notably, high-expression IL-10 genotypes (-1082GG) and low-expression IL-6 genotypes (-174AA) were significantly associated with MCPyV detection (p = 0.048 and p = 0.015, respectively). Conclusion: MCPyV prefer-entially localizes to NMSC lesions, particularly in individuals with immunogenetic profiles favoring viral persistence. Given the unclear role of MCPyV in NMSC patho-genesis, our findings call for comprehensive studies to determine whether the lesional environment facilitates viral persistence or reflects a more complex viral–host interac-tion with potential implications in cutaneous oncogenesis.