<p>Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, originating from the squamous cells of the oral mucosa. The global occurrence is significant and is closely linked to smoking, alcohol use, and HPV infection, with a generally poor prognosis, highlighting the importance of early detection and treatment. Integrins are heterodimeric transmembrane receptors composed of α and β subunits, forming a recognized family of about 24 subtypes. ITGA3 and ITGA5, integrin family members, are crucial for cytoskeletal organization, cell migration, proliferation, and survival. ITGA3 acts as a cell membrane adhesion molecule, engaging with laminin family extracellular matrix proteins linked to tumors. ITGA5 and β1 combine to form a receptor for extracellular fibronectin, playing a role in malignant tumor cells and vasculature. Our study identified that ITGA3 and ITGA5 were overexpressed in oral cancer tissues, correlating with a significantly poorer prognosis for patients exhibiting high levels of these integrins. Further, we found that ITGA3 and ITGA5 were associated with the infiltration of a variety of immune cells as well as with the expression of a variety of immune checkpoints and ferroptosis-related genes. Our findings indicate that ITGA3 and ITGA5 expression levels are associated with the sensitivity to commonly used oral cancer treatments. These findings suggest that ITGA3 and ITGA5 could be potential targets for the prognosis, diagnosis, and treatment of OSCC.</p>