Exploring beyond Common Cell Death Pathways in Oral Cancer: A Systematic Review

Simple Summary Oral squamous cell carcinoma (OSCC), the major malignant tumor of the oral cavity, is one of the most common cancers in the world. Its treatment response rate mainly depends on the clinical stage, and there is an urgent need to develop more effective therapeutic alternatives. Our understanding of the molecular mechanisms regulating different types of tumor cell death is evolving and providing new perspectives to increase the efficacy of conventional therapies combined with the manipulation of signaling cascades to promote tumor cell death. In this systematic review, we provide an overview of emerging types of cell death in OSCC, highlighting opportunities to capitalize on this increased understanding to inform diagnosis, prognosis and treatment.Abstract Oral squamous cell carcinoma (OSCC) is the most common and lethal type of head and neck cancer in the world. Variable response and acquisition of resistance to traditional therapies show that it is essential to develop novel strategies that can provide better outcomes for the patient. Understanding of cellular and molecular mechanisms of cell death control has increased rapidly in recent years. Activation of cell death pathways, such as the emerging forms of non-apoptotic programmed cell death, including ferroptosis, pyroptosis, necroptosis, NETosis, parthanatos, mitoptosis and paraptosis, may represent clinically relevant novel therapeutic opportunities. This systematic review summarizes the recently described forms of cell death in OSCC, highlighting their potential for informing diagnosis, prognosis and treatment. Original studies that explored any of the selected cell deaths in OSCC were included. Electronic search, study selection, data collection and risk of bias assessment tools were realized. The literature search was carried out in four databases, and the extracted data from 79 articles were categorized and grouped by type of cell death. Ferroptosis, pyroptosis, and necroptosis represented the main forms of cell death in the selected studies, with links to cancer immunity and inflammatory responses, progression and prognosis of OSCC. Harnessing the potential of these pathways may be useful in patient-specific prognosis and individualized therapy. We provide perspectives on how these different cell death types can be integrated to develop decision tools for diagnosis, prognosis, and treatment of OSCC.