Neuroimmunology of Oral Cancer: Tumor Progression, Systemic Inflammation, and Neural Circuit Dysfunction from the Cerebellum to the Frontal Cortex.

Oral cancer, predominantly oral squamous cell carcinoma, ranks among the ten most common malignancies worldwide and carries a disproportionate burden across South and South-East Asia, where tobacco, betel quid, areca nut, and alcohol use remain widespread. Although conventionally framed as a localised disease, accumulating evidence indicates that oral cancer may behave as a systemic condition with under-recognised neuroimmunological consequences. This narrative review synthesises current literature on the pathways through which tumour-driven inflammation extends beyond the primary site to influence central nervous system function, with particular attention to the cerebellum and frontal cortex. We outline how the tumour microenvironment sustains a chronic inflammatory state, releasing pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α that may compromise the integrity of the blood-brain barrier, activate microglia and disturb synaptic plasticity. Within the cerebellum, perineural invasion, paraneoplastic degeneration, and rare metastatic spread appear to be linked to motor incoordination, ataxia, and the cerebellar cognitive affective syndrome. Within the frontal cortex, systemic inflammation is associated with a so-called sterile chemobrain, encompassing executive dysfunction, attentional and working-memory deficits, depression and impaired decision-making, even in the absence of chemotherapy. We further appraise emerging biomarker and neuroimaging evidence, including salivary and serum cytokine profiles, structural and functional MRI changes, and PET markers of microglial activation, that together suggest a measurable peripheral-to-central signalling axis. The review highlights the limitations of the present evidence, which rests substantially on small studies, case reports and extrapolation from other malignancies, and underscores the need for longitudinal and mechanistic research. Recognising oral cancer as a potential systemic neuroimmune disorder may support earlier neurocognitive assessment, biomarker-guided risk stratification and neuroprotective intervention, with the aim of improving survivorship and quality of life.