The development of cancer can be significantly influenced by collaborative interactions of neoplastic cells with multiple cell types in the tumor microenvironment, particularly cells of the innate and adaptive immune system.Tumor-associated macrophages (TAMs), derived from circulating blood monocytes, often make up a significant part of infiltrating inflammatory ceils in the tumor microenvironment and, in most cases, promote tumor growth and metastasis.In the development of neck and head squamous cell carcinoma (HNSCC) and oral cancer, recruitment and infiltration of TAMs, but not T lymphocytes, into and around cancer tissues have been shown to be associated with tumor aggressiveness and poor prognosis.However, it is unknown to what extent chemotactic molecules contribute to the migration of inflammatory cells, since the monocyte chemotactic protein-1 (MCP-1) expressing tumor cells are rare and uncorrelated with immune cell migration in HNSCC biopsy samples.Our recent work, using immunofluorescence microscopy on oral cancer biopsies in vivo, has discovered that premalignant cells in the carcinoma in situ lesion predominantly produce human β-defensin-3 (hBD-3), correlating with specific recruitment and infiltration of macrophages in the lesion site, without involvement of MCP-1.Moreover, HEK293 cells overexpressing hBD-3 generate tumors containing massive infiltrating macrophages in athymic nude mice, while hBD-3-knockdown cells fail to recruit macrophages.Animals injected with hBD-3-knockdown cells form much smaller tumors and the incidence of tumor formation is less frequent compared to that injected with hBD-3 overexpression cells.Further, hBD-3 significantly chemoattracts monocytic THP-1 ceils in vitro and a specific antagonist to the C-C chemokine receptor, CCR2, blocks hBD-3-induced cell migration, suggesting the involvement of CCR2 in hBD-3 induction of monocyte migration.HBD-3 was originally identified as an innate immune antimicrobial peptide produced by psoriatic skin lesions.More recently, hBD-3 has been shown to be involved in modulating immune responses, such as induction of immune cells migration, activation of antigen-presenting cells, and antagonism of chemokine receptor CXCR4.Our data indicate that hBD-3 may act as a motility signal to selectively induce migration and infiltration of macrophages to the dysplastic lesion, leading to the progression of oral cancer.