In recent decades, understanding tumorigenesis and the complex interaction between the host and the immune system has been the pillar for significant advances in anticancer therapy. Conventional anticancer therapy (e.g., cut, burn, and cytotoxic drugs) involves multiple targeting of tumor cells. However, the tumor tissue microenvironment can present a dysregulated, stimulating, or subverted immune response which, in turn, reveals pro-tumor activities favoring tumor expansion and progression. Recently, new potential targets have been identified based on immunomodulatory therapies, which are crafted to re-establish the host anti-tumoral immune response. Clinicians should fully understand the intricate interactions between carcinogens, the tumor milieu, the immune system, and traditional anticancer therapies in order to progress and to overcome the refractory/recurrent challenges and morbidity of the disease. Thus, in this article, we highlight the complex milieu of the oral cancer immune response, pointing out potential therapeutic immunotargets for oral squamous cell carcinomas. The impact of traditional anticancer therapy on the immune system is also outlined.