Relationship between inflammation, depression, and immune surveillance in oral cancer

Table 2 Integrated inflammation-depression-immune surveillance axis in oral cancer

Domain	Key mediators/cells	Molecular/biological mechanism	Effect on immune surveillance	Impact on tumor microenvironment	Clinical implication
Chronic inflammation	IL-6, TNF-α, IL-1β, CRP	Persistent activation of NF-κB and STAT3 pathways leading to transcription of pro-survival and pro-inflammatory genes	Suppresses cytotoxic T-cell activity; promotes T-cell exhaustion; alters antigen presentation	Promotes angiogenesis (VEGF ↑), EMT, extracellular matrix degradation, and tumor invasion	Associated with poor prognosis, aggressive tumor phenotype, and resistance to therapy
Tumor-induced immune dysregulation	NK cells ↓, CD8+ T cells ↓, Tregs ↑, dendritic cells dysfunctional	Immune editing (elimination → equilibrium → escape); upregulation of immune checkpoints (PD-1/PD-L1 axis)	Reduced tumor cell recognition and killing; impaired adaptive immune activation	Establishes immunosuppressive microenvironment; supports tumor survival and immune evasion	Reduced response to immunotherapy; increased recurrence risk
Depression-associated neuroendocrine changes	HPA axis, cortisol, catecholamines	Chronic HPA activation leading to cortisol dysregulation and glucocorticoid resistance in immune cells	Decreased NK cell cytotoxicity; altered T-cell responses; impaired immune signaling	Enhances inflammatory signaling; indirectly supports tumor-promoting pathways	Poor treatment adherence, reduced survival, increased systemic inflammation
Depression-induced inflammation	IL-6 ↑, TNF-α ↑, CRP ↑	Cytokine-mediated signaling from peripheral immune system to CNS; bidirectional brain–immune interaction	Further suppresses immune surveillance; promotes immune exhaustion	Amplifies tumor-associated inflammation; sustains pro-tumorigenic environment	Biomarker potential for prognosis and disease monitoring
Neuroimmune interaction	Sympathetic nervous system, β-adrenergic signaling	Catecholamine-mediated modulation of immune cells and cytokine production	Alters immune cell trafficking and reduces antitumor activity	Increases angiogenesis, tumor cell migration, and invasion	Potential target for beta-blocker-based adjunct therapies
Feedback loop (inflammation ↔ depression)	Cytokines + neural signaling	Peripheral inflammation affects neurotransmitters (serotonin, dopamine); CNS influences immune response	Creates chronic immune dysregulation state	Sustains tumor-promoting inflammation and immune escape	Explains interpatient variability in progression and outcomes
Integrated triad effect	Combined axis	Persistent inflammatory activation without effective immune control	Functional immune paralysis despite activation	Accelerated tumor progression, invasion, and metastasis	Defines high-risk biological phenotype; supports need for integrated management
Therapeutic targeting opportunities	Anti-inflammatory drugs, antidepressants, immunotherapy	Modulation of cytokines, HPA axis normalization, immune checkpoint inhibition	Restoration of immune surveillance potential	Reduction in tumor-promoting inflammation	Basis for integrative oncology and personalized treatment strategies

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; IL-1β: Interleukin-1 beta; CRP: C-reactive protein; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; VEGF: Vascular endothelial growth factor; EMT: Epithelial–mesenchymal transition; NK cells: Natural killer cells; Tregs: Regulatory T cells; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; HPA axis: Hypothalamic-pituitary-adrenal axis; CNS: Central nervous system.