Dynamic Changes in Macrophage Infiltration and Polarization During Oral Carcinogenesis and Tumor Progression

Background: Oral epithelial dysplasia (OED) is a precursor lesion to oral squamous cell carcinoma (OSCC). However, the dynamic changes in macrophage infiltration and polarization during oral carcinogenesis remain unclear. This study investigated macrophage infiltration and polarization during the progression from OED to OSCC, with particular emphasis on changes in the tumor microenvironment (TME). Methods: Human OED and OSCC specimens were immunohistochemically examined using macrophage markers representing the M0, M1, and M2 phenotypes. In addition, an indirect co-culture model using the OSCC cell lines HSC-2 and HSC-3 and RAW264.7 macrophages was established to evaluate macrophage migration and polarization in vitro. Results: Both M1- and M2-like macrophage populations increased with the histological progression of OED. M1-like macrophages predominated throughout the dysplastic stage, whereas M2-like macrophages became the predominant population after early stromal invasion. In OSCC, well-differentiated squamous cell carcinoma (SCC) was associated with greater macrophage infiltration, whereas poorly differentiated SCC was associated with a more M2-like macrophage polarization. Conclusions: The immune microenvironment begins to remodel during the precancerous stage of oral carcinogenesis. Macrophage recruitment and polarization differ according to the histological differentiation of OSCC, highlighting the importance of considering intratumoral histological heterogeneity when evaluating macrophage dynamics within the TME.