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

Table 1 Summary of studies utilized in the review

No.	Ref.	Study summary
1	Barroso et al[9], 2025	Explores the molecular and genetic basis of oral cancer, including mutations, signaling pathways, and genomic instability. Discusses how these alterations contribute to tumor initiation and progression. Highlights potential biomarkers for personalized diagnosis and targeted therapy
2	Mascolo et al[10], 2012	Focuses on epigenetic dysregulation such as DNA methylation and histone modification in oral cancer. Explains how these reversible changes alter gene expression without changing DNA sequence. Suggests epigenetic markers as diagnostic and therapeutic targets
3	Jiang et al[11], 2019	Reviews the carcinogenic mechanisms of tobacco in oral squamous cell carcinoma. Describes pathways involving oxidative stress, DNA damage, and mutagenesis. Emphasizes tobacco’s role in tumor initiation and progression
4	Brailo et al[12], 2012	Investigates levels of inflammatory cytokines (IL-1β, IL-6, TNF-α) in saliva and serum. Demonstrates their elevation in oral cancer and leukoplakia patients. Suggests their use as potential biomarkers for early detection
5	Bi and Tian[13], 2017	Describes NK cell exhaustion and its impact on immune surveillance. Explains how chronic stimulation reduces cytotoxic function. Highlights implications for cancer immune evasion
6	Yang et al[14], 2023	Reviews the roles of immune cells (T cells, NK cells, macrophages) in cancer immunotherapy. Discusses their interactions within the tumor microenvironment. Also explores advanced drug delivery strategies targeting these cells
7	Huang et al[15], 2025	Examines CAFs and their heterogeneity. Describes their role in tumor growth, invasion, and immune modulation. Highlights therapeutic strategies targeting CAF signaling pathways
8	Hao et al[16], 2026	Focuses on stromal cell contributions to oral cancer progression and metastasis. Explains tumor-stroma interactions and their role in recurrence. Suggests targeting stromal components for therapy
9	Ling et al[17], 2021	Discusses EMT in oral cancer. Explains how EMT promotes invasion, metastasis, and therapy resistance. Highlights challenges and therapeutic opportunities
10	Grivennikov et al[18], 2010	Explores crosstalk between STAT3 and NF-κB signaling pathways. Shows how these pathways regulate inflammation and cancer progression. Emphasizes their synergistic role in tumor development
11	Kim et al[19], 2007	Introduces the concept of cancer immunoediting. Describes phases: Elimination, equilibrium, and escape. Explains how tumors evade immune surveillance over time
12	Wang et al[20], 2024	Reviews interactions between innate and adaptive immune systems. Explains how these systems coordinate responses against tumors. Highlights their importance in immunotherapy outcomes
13	Portale and Di Mitri[21], 2023	Examines NK cell dysfunction in cancer. Describes mechanisms leading to reduced cytotoxic activity. Discusses therapeutic strategies to restore NK cell function
14	Xiao et al[22], 2023	Focuses on impaired dendritic cell function in tumor microenvironment. Explains how this reduces antigen presentation and immune activation. Highlights its role in tumor immune evasion
15	Whiteside[23], 2012	Discusses Tregs in cancer. Explains their role in suppressing anti-tumor immune responses. Highlights their contribution to immune tolerance in tumors
16	Budi and Farhood[24], 2023	Reviews therapeutic strategies targeting tumor microenvironment in oral cancer. Explains interactions between cancer cells and surrounding stroma. Suggests multi-targeted treatment approaches
17	Lin et al[25], 2024	Describes regulation of PD-1/PD-L1 immune checkpoint pathway. Explains its role in tumor immune escape. Highlights therapeutic blockade strategies in cancer treatment
18	Sharma et al[26], 2025	Examines prevalence of oral precancerous lesions in tobacco and areca nut users. Provides epidemiological data linking habits to disease. Emphasizes importance of early screening
19	Niklander[27], 2021	Reviews inflammatory mediators involved in oral cancer. Explains their role in tumor initiation and progression. Discusses their diagnostic and prognostic potential
20	Bagan et al[28], 2016	Investigates IL-6 levels in proliferative verrucous leukoplakia. Shows association with disease severity. Suggests IL-6 as a biomarker for malignant transformation
21	Hibino et al[29], 2021	Explores inflammation-induced tumorigenesis and metastasis. Describes molecular pathways linking chronic inflammation to cancer. Highlights therapeutic targets in inflammatory signaling
22	Heinrich et al[30], 2012	Links inflammation with EMT and carcinogenesis. Explains how inflammatory signals promote tumor progression. Emphasizes microenvironmental influence on cancer behavior
23	Speksnijder et al[31], 2021	Studies long-term depression in oral cancer patients post-treatment. Identifies psychosocial and clinical risk factors. Highlights need for mental health support in survivorship care
24	Alotiby[32], 2024	Reviews immunological effects of stress. Explains how stress alters immune cell function and cytokine production. Links chronic stress to disease susceptibility
25	Peng et al[33], 2026	Examines stress, inflammation, and resilience in oral cancer patients. Highlights bidirectional relationship between psychological stress and immune response. Suggests integrated care approaches
26	Cao et al[34], 2025	Explores how depression alters inflammatory cytokines. Describes their role in cancer development. Suggests psychoneuroimmunological pathways in carcinogenesis
27	Sforzini et al[35], 2019	Discusses kynurenine pathway in cancer and depression. Explains how inflammation drives metabolic changes. Links pathway to immune suppression and mood disorders
28	Young and Singh[36], 2018	Reviews biological mechanisms of cancer-induced depression. Explains roles of cytokines and neuroendocrine changes. Highlights impact on patient outcomes
29	Lempesis et al[37], 2023	Reviews role of stress in cancer pathogenesis. Explains hormonal and immune pathways involved. Emphasizes stress as a contributing risk factor
30	Balcerowska et al[38], 2025	Explores effects of stress on immune system function. Describes alterations in immune responses under chronic stress. Highlights implications for disease progression
31	Jiang et al[39], 2025	Meta-analysis of inflammatory markers associated with depression. Identifies key cytokines linked to depressive states. Suggests inflammation as a biological basis for depression
32	Wang[40], 2020	Explains heterogeneity in anti-tumor immune responses. Discusses variability in patient outcomes. Suggests personalized immunotherapy approaches
33	Zhou et al[41], 2026	Reviews combination of radiotherapy and immunotherapy. Explains immunomodulatory effects of radiation. Highlights future clinical applications
34	Yu et al[42], 2025	Discusses depression management in cancer patients. Reviews therapeutic strategies and clinical implications. Emphasizes integrated oncology care
35	Kaur et al[43], 2025	Reviews emerging targeted therapies in oral cancer. Includes novel and repurposed drugs. Highlights future directions in precision oncology
36	Anghel et al[44], 2025	Reviews psychological interventions in oncology. Discusses effectiveness of different therapeutic approaches. Highlights future trends in psycho-oncology care

IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; NK: Natural killer; CAFs: Cancer-associated fibroblasts; EMT: Epithelial-to-mesenchymal transition; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor kappa B; Tregs: Regulatory T cells; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death protein 1.

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.