Background <p>Oral squamous cell carcinoma (OSCC) has a poor prognosis due to late-stage diagnosis, early metastasis, and resistance to treatment. OSCC is heavily influenced by its tumor microenvironment (TME), especially the stromal cell populations, which support tumor growth and contribute to recurrence and treatment resistance. Despite the tumor-stroma ratio being linked to disease progression, it is not yet part of standard staging. Moreover, it is not directly addressed by current treatments, including surgery, radiation, and chemotherapy.</p> Main body <p>Among the diverse stromal components, specific cell types play distinct yet complementary roles. Pericytes regulate angiogenesis and vascular stability, while their dysfunction causes immature vessels and neovascularization. Anti-angiogenic therapy restores vascular integrity, increases pericyte coverage, and improves drug delivery. MSCs promote tumor progression through cytokine release, angiogenesis, and extracellular matrix remodeling, with their effects varying based on their origin. CAFs are the predominant non-immune cells in tumors, playing a critical role in tumor initiation, progression, and metastasis by remodeling the extracellular matrix, secreting cytokines, and promoting epithelial-mesenchymal transition. Endothelial cells facilitate metastasis by promoting angiogenesis, endothelial-to-mesenchymal transition, and immune evasion through VEGF, miRNAs, and Rho/YAP and TGF-β signaling, enhancing tumor growth, migration, and chemoresistance.</p> Conclusion <p>Collectively, stromal cells in OSCC, including pericytes, MSCs, CAFs, and endothelial cells, play a critical role in tumor progression, metastasis, and drug resistance, highlighting the potential for targeting these cells in future therapies to improve clinical outcomes and patient prognosis.</p>