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

Abstract

Oral cancer is characterized by complex interactions between tumor biology, host immune surveillance, and systemic inflammatory processes. Increasing evidence indicates that depressive symptoms in patients with oral cancer are associated with persistent inflammatory activation and immune dysregulation, extending beyond psychosocial morbidity to biologically relevant alterations in antitumor defense. Depression is linked to elevated circulating pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and C-reactive protein, alongside neuroendocrine imbalance that influences immune cell trafficking and function. In oral cancer, this inflammatory milieu coincides with impaired innate and adaptive immune mechanisms critical for tumor surveillance, including reduced natural killer cell cytotoxicity, altered T-lymphocyte subsets, diminished antigen presentation capacity, and increased expression of immune exhaustion markers. Chronic inflammation associated with depressive symptoms may further exacerbate tumor-promoting processes, such as angiogenesis, epithelial-mesenchymal transition, and immune evasion within the oral tumor microenvironment. The convergence of inflammation, depression, and immune surveillance constitutes a biologically significant axis in oral cancer, potentially shaping disease progression, treatment response, and clinical outcomes.

Key Words: Depression; Immune surveillance; Inflammation; Oral cancer; Tumor microenvironment

Core Tip: Inflammation, depression, and immune surveillance constitute a biologically integrated axis in oral cancer. Chronic inflammatory activation and depression-associated neuroendocrine dysregulation impair antitumor immune responses, leading to reduced immune surveillance, tumor progression, and immune evasion. Recognition of this integrated axis provides a mechanistic framework for disease progression and supports the development of improved prognostic models and integrative therapeutic strategies.

INTRODUCTION

Oral cancer remains a significant global health burden with high morbidity and mortality, especially in populations with widespread use of tobacco, alcohol, and betel quid. According to GLOBOCAN 2022, oral cancer ranks 15^th in global cancer-related mortality, with approximately 389846 new cases and 188438 deaths worldwide[1]. Despite advances in diagnosis and treatment, survival outcomes remain unsatisfactory. The 5-year survival rate generally ranges from 40%-60%, with some studies reporting even lower rates, highlighting challenges in early detection and disease management[2]. In addition, survivors often experience considerable impairment in quality of life due to functional limitations and aesthetic concerns. These findings suggest that improvements in survival in recent decades have been limited. While oral carcinogenesis has traditionally been linked to local environmental and behavioral risk factors, it is now evident that tumor progression is also influenced by interactions between tumor biology, host immunity, and systemic inflammation[3,4]. Chronic exposure to carcinogens such as tobacco leads to persistent inflammatory signaling, which promotes tumor development through increased cellular proliferation, angiogenesis, and suppression of antitumor immune responses. Elevated levels of inflammatory mediators, such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP), have been reported in oral cancer patients, contributing to a tumor-promoting environment characterized by immune alteration and reduced immune surveillance. The physiological and pathological changes in oral cancer patients are also accompanied by psychological changes, as depression is frequently observed in patients, often related to treatment effects, functional deficits, and psychosocial stress. Beyond just its psychological impact, depression has important biological consequences, which can reduce natural killer (NK) cell activity, alter T-cell responses, and disrupt cytokine balance. This leads to weakening of the host defense mechanisms. The chronic inflammatory microenvironment plays a critical role in oral health progression to malignancy. According to Shalapour and Karin[4], cancer-associated inflammation can be viewed as a dynamic phenomenon during which continuous immune system activation leads to its transformation from tumor suppression to tumor promotion. As shown by Swenson et al[5], the process begins with the development of an inflammatory microenvironment caused by carcinogens like tobacco. Swenson et al[5] found that tobacco carcinogens increase the expression of AP-1-dependent pro-angiogenic cytokines. It should also be noted that the localized inflammation of a tumor has systemic consequences. As found by Azimudin et al[6], the TNF-α levels are increased in patients with oral squamous cell carcinoma. Apart from changes in physiology, oral cancer is also associated with a notable psychological burden. According to Kung et al[7], patients with this pathology have a greater likelihood of depression. Interestingly, while often viewed as psychological in nature, depression been associated with significant physiological effects. As shown by Hole et al[8], patients with depression exhibit immune dysregulation resembling that found in cancer patients. However, the role of carcinogen-induced inflammatory pathway and depression-associated immune changes in modulating immune surveillance and cancer progression in the oral cavity remains poorly understood.

OBJECTIVE

The primary objective of this review is to summarize the current research findings on the biological pathways involving inflammation, depression, and immune surveillance in oral cancer. The overarching goal is to transform the traditional medical practice that focuses only on psychological or biological aspects into one that considers the overall biological system impacting disease development and patient health in oral cancer.

RESEARCH QUESTIONS

How do carcinogen-induced inflammatory mediators and depression-associated neuroendocrine changes synergistically modulate the oral tumor microenvironment? Through what specific biological pathways does the inflammation-depression axis impair innate and adaptive immune surveillance in oral cancer patients? Can the recognition of this integrated triad serve as a foundation for developing more precise prognostic models and multifaceted therapeutic strategies?

SEARCH STRATEGY

Research design

This is a minireview synthesizing current literature on the biological intersection of inflammation, depression, and immune surveillance in oral cancer.

Search strategy

A structured literature search was performed using the PubMed database to identify relevant studies exploring the relationship between oral cancer, inflammation, immune surveillance, and depression. Keywords and Medical Subject Headings terms, including “oral cancer”, “oral squamous cell carcinoma”, “inflammation”, “cytokines”, “immune surveillance”, “tumor microenvironment”, “depression”, and “psychoneuroimmunology”, were used in various combinations with Boolean operators (AND, OR). The search was limited to English-language articles published from 2005 to 2026. Reference lists of selected articles were manually screened to identify additional pertinent studies. This approach ensured a comprehensive and focused synthesis of current evidence relevant to the topic.

Selection of articles

The initial literature search yielded 174 articles. After removal of duplicate records, 168 articles remained for screening. Titles and abstracts were subsequently reviewed, resulting in the exclusion of studies not relevant to the scope of the review. Following this screening process, 90 articles were selected for full-text assessment. After detailed evaluation, 36 studies that met the inclusion criteria were ultimately included in the review for qualitative synthesis (Table 1).

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.

ORAL CANCER BIOLOGY AND THE TUMOR MICROENVIRONMENT

Oral cancer develops through a multistep process involving the accumulation of genetic and epigenetic alterations over time. Frequently reported changes include mutations in tumor suppressor genes such as TP53, along with the dysregulation of pathways that control cell proliferation, differentiation, and apoptosis[9,10]. These alterations drive the transformation of normal oral epithelium into dysplastic lesions, and eventually, invasive carcinoma. However, these molecular events alone do not fully explain the clinical variability seen in oral cancer, as tumor behavior is also shaped by the surrounding microenvironment. Chronic inflammation plays a central role in this process, particularly in individuals with prolonged exposure to carcinogens, such as tobacco and related products[11]. Persistent inflammatory signaling leads to the generation of reactive oxygen species, DNA damage, and activation of pathways that promote cell survival and proliferation. As demonstrated in the study by Brailo et al[12], patients with oral cancer exhibit significantly elevated salivary concentrations of interleukin 1 beta (IL-1β) and IL-6 compared with those with oral leukoplakia and healthy controls (P < 0.05), highlighting the presence of a localized inflammatory response. Inflammatory mediators such as IL-6, TNF-α, and other cytokines, are commonly elevated and contribute to angiogenesis, tumor growth, and resistance to apoptosis. This sustained inflammatory state creates conditions that favor tumor initiation and progression. The tumor microenvironment in oral cancer is composed of cancer cells, immune cells, and stromal elements that interact in a dynamic and continuous manner. Immune cells, such as T lymphocytes, NK cells, and macrophages, are actively recruited to the tumor site; however, their function is often altered. T cells may become functionally suppressed or exhausted, NK cell cytotoxicity is reduced, and macrophages frequently adopt a phenotype that supports tumor growth, angiogenesis, and tissue remodeling[13,14]. In addition, regulatory immune mechanisms within the tumor further dampen effective antitumor responses. Stromal components, including cancer-associated fibroblasts, endothelial cells, and extracellular matrix elements, also significantly contribute to tumor progression[15-17]. These cells secrete growth factors, cytokines, and matrix-degrading enzymes that facilitate local invasion, angiogenesis, and metastatic spread. The interactions between these cellular components are mediated through key signaling pathways such as nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), which link inflammatory signals with tumor cell survival, proliferation, and immune modulation[18]. As these processes continue, tumor cells acquire the ability to evade immune detection, a phenomenon referred to as immune escape. This involves mechanisms such as reduced antigen presentation, increased production of immunosuppressive cytokines, and the creation of a local environment that limits effective immune surveillance (Figure 1).

Figure 1 Role of inflammatory mediators in oral cancer progression and prognosis.

IMMUNE SURVEILLANCE IN ORAL CANCER

Immune surveillance is a fundamental host defense mechanism that identifies and eliminates emerging malignant cells. In oral cancer, this process follows the classical phases of immunoediting: Elimination, equilibrium, and escape[19]. During the elimination phase, innate and adaptive immune components work synergistically to recognize and destroy transformed cells. However, as the tumor evolves, selective pressures enable the survival of less immunogenic variants, leading to an equilibrium state, and ultimately to immune escape, where tumor cells evade immune destruction and proliferate unchecked. The innate immune system forms the first line of defense, with NK cells and dendritic cells playing pivotal roles[20]. NK cells exert cytotoxic effects independent of antigen presentation by recognizing stress-induced ligands on tumor cells. However, in oral cancer, NK cell activity is often reduced, limiting early antitumor responses[21]. Dendritic cells, responsible for antigen capture and presentation, are frequently functionally impaired within the tumor microenvironment, leading to suboptimal activation of adaptive immunity[22]. Adaptive immune responses, particularly T-lymphocyte-mediated mechanisms, are important for sustained tumor control. Cytotoxic CD8+ T cells directly target tumor cells, while CD4+ T helper cells coordinate immune responses. In oral cancer, there is an imbalance in T-cell subsets, characterized by reduced effector T-cell function and increased regulatory T cells (Tregs), which suppress antitumor immunity. Additionally, chronic antigen exposure leads to T-cell exhaustion, marked by diminished cytokine production and upregulation of inhibitory receptors[23,24]. A critical mechanism of immune evasion in oral cancer involves immune checkpoint pathways, particularly the programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) axis, which inhibits T-cell activation and promotes immune tolerance[25]. Tumor-associated macrophages further contribute to immune suppression by adopting phenotypes that support tumor growth, angiogenesis, and suppression of cytotoxic immune responses. These alterations collectively impair effective immune surveillance, allowing tumor cells to persist and progress. Clinically, this has significant implications, as immune dysfunction not only facilitates disease progression but also influences response to emerging immunotherapeutic strategies in oral cancer.

INFLAMMATION IN ORAL CANCER

Chronic inflammation is a well-established hallmark of cancer and plays a pivotal role in the initiation and progression of oral cancer. In the oral cavity, persistent exposure to carcinogenic stimuli such as tobacco, alcohol, areca nut, and microbial pathogens leads to sustained inflammatory responses. A study by Sharma et al[26] found that oral potentially malignant disorders, such as leukoplakia and oral submucous fibrosis, are characterized by a chronic inflammatory milieu that predisposes the patient to malignant transformation. Inflammation contributes to oral carcinogenesis through multiple interconnected mechanisms. Persistent inflammatory signaling promotes the generation of reactive oxygen and nitrogen species, leading to DNA damage, genomic instability, and accumulation of oncogenic mutations. Simultaneously, inflammatory mediators stimulate cellular proliferation, inhibit apoptosis, and facilitate tissue remodeling, thereby creating a pro-tumorigenic environment. Key pro-inflammatory cytokines, including IL-6, TNF-α, IL-1β, and CRP, are frequently elevated in patients with oral cancer[3,27]. Bagan et al[28] demonstrated that both serum and salivary IL-6 levels are significantly elevated in patients with oral squamous cell carcinoma and proliferative verrucous leukoplakia compared with healthy controls, with the highest levels observed in malignant cases. These mediators not only sustain local inflammation but also contribute to systemic inflammatory responses. At the molecular level, signaling pathways such as NF-κB and STAT3 are persistently activated, driving transcription of genes involved in cell survival, proliferation, angiogenesis, and immune modulation. Inflammation also plays a critical role in tumor progression and metastasis. It promotes angiogenesis through vascular endothelial growth factor induction, enhances epithelial-mesenchymal transition (EMT), and facilitates invasion by degrading extracellular matrix components[29,30]. Furthermore, the inflammatory microenvironment contributes to immune suppression by altering immune cell function and promoting the recruitment of immunosuppressive cell populations. Importantly, inflammation in oral cancer exists at both local and systemic levels. While the local tumor microenvironment drives direct tumor-promoting effects, systemic inflammation reflects broader host responses that can influence disease progression and patient outcomes. This dual role highlights inflammation as a central link between tumor biology, immune dysregulation, and emerging systemic factors such as depression in oral cancer.

DEPRESSION IN ORAL CANCER

Depression is a common yet underrecognized comorbidity in oral cancer, with prevalence rates significantly exceeding those of the general population. While traditionally viewed as a psychological response to diagnosis, it is increasingly recognized as a biological condition with profound implications for cancer biology. Speksnijder et al[31] conducted a study of 141 patients and found that 24.8% reported depression before oncological treatment, noting that patients with oral cancer exhibit a higher prevalence of depressive symptoms compared with healthy controls. This state is characterized by the chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, leading to dysregulated cortisol dynamics and increased catecholamine release. Immune cells may develop glucocorticoid resistance over time, where they no longer respond to the anti-inflammatory signals of cortisol, thereby perpetuating a state of chronic low-grade systemic inflammation[32,33]. Consequently, patients frequently express elevated pro-inflammatory biomarkers, including IL-6, TNF-α, and CRP. Importantly, this relationship is bidirectional: While depression induces inflammatory activation, the existing tumor-associated inflammatory milieu can further exacerbate depressive symptoms through neural and humoral signaling to the brain. In oral cancer, this reciprocal cycle may amplify existing inflammatory processes, influence neurotransmitter metabolism, and promote immunosuppressive pathways that interfere with effective immune surveillance[34-36]. Recognizing depression as a biologically relevant driver of inflammation, rather than solely a psychosocial issue, is essential for understanding how neuroendocrine regulation and immune function converge to influence tumor behavior and disease progression.

COMBINED INFLUENCE OF INFLAMMATION, DEPRESSION, AND IMMUNE SURVEILLANCE IN ORAL CANCER

Inflammation, depression, and immune surveillance represent interconnected biological processes that together influence oral cancer progression. While each has been independently associated with tumor behavior, their combined interaction offers a more precise framework for understanding disease dynamics beyond conventional tumor-centric models. Oral cancer develops within a pre-existing inflammatory microenvironment driven by carcinogenic exposures and tumor-derived mediators. This baseline state is not static, but it is modulated by systemic host factors. Depression introduces sustained neuroendocrine and inflammatory alterations that can amplify this environment. The result is a state of persistent immune activation that does not translate into effective tumor control. A key feature of this convergence is the functional imbalance between inflammation and immune surveillance. Although inflammatory signaling remains elevated, the efficiency of antitumor immune responses is reduced. This creates a biological condition in which tumor-promoting pathways, such as angiogenesis, cellular proliferation, and tissue invasion, are supported, while immune-mediated tumor elimination is insufficient. Tumor-associated inflammation can influence central regulatory pathways and contribute to depressive symptoms, while depression can further modulate inflammatory and immune responses. This reciprocal interaction establishes a reinforcing cycle that may contribute to variability in tumor progression and treatment response among patients. From an interpretative standpoint, this triad can be viewed as a functional axis within oral cancer biology, where systemic host factors and local tumor processes are closely integrated. Recognizing this axis shifts the perspective from isolated mechanisms to coordinated biological interactions, offering a more nuanced understanding of disease behavior. This integrated view has potential clinical relevance. It suggests that variations in inflammatory status and psychological health may act as modifiers of immune competence and tumor progression[37,38]. Addressing these interconnected pathways may therefore provide additional opportunities to improve patient outcomes beyond conventional oncologic approaches (Figure 2).

Figure 2 Integrated interaction between inflammation, depression, and immune surveillance in oral cancer. HPA: Hypothalamic-pituitary-adrenal; NK: Natural killer; CNS: Central nervous system.

Specific modulators of the inflammation-depression immunity axis in oral carcinogenesis

Unlike systemic malignancies, the oral tumor microenvironment is subjected to continuous insults due to the oral microbiome and chemical trauma. Among oral periodontopathogens, Porphyromonas gingivalis and Fusobacterium nucleatum have been linked to oral cancer development via pro-inflammatory cascade activation. Specifically, Porphyromonas gingivalis can activate the NF-κB pathway in oral epithelium, resulting in increased expression of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. On the other hand, Fusobacterium nucleatum drives tumor development by increasing levels of IL-6 and IL-8 and changing immune cell composition. Such microbiome-induced inflammatory processes lead to a chronically primed state of inflammation that results in immune exhaustion, which manifests as impaired NK cell activity and cytotoxic T-cell responses. Apart from the effects of microbes, exposure to cancer-causing agents specific to certain regions, such as areca nut, betel quid, and chewing tobacco, cause unique inflammation and fibrosis responses in the oral mucosa. The effect of such exposures is the elevation of transforming growth factor beta, IL-6, and reactive oxygen species, causing EMT, stromal fibrosis, and activation of inflammatory transcription pathways such as NF-κB and STAT3. Unlike systemic exposure to carcinogens in most types of cancer, the regional inflammatory environment of oral cancer leads to a tumor microenvironment that causes T-cell immunosuppression through Treg proliferation[24,26,27]. Another distinctive aspect of oral cancer that significantly contributes to the onset of depression or any psychological disorder is its effects on basic activities like speech, chewing, and appearance. Psychosocial factors stimulate neuroendocrine systems, especially the HPA axis, causing excessive production of cortisol, resulting in glucocorticoid resistance in immune cells, and raising the levels of circulating IL-6 and TNF-α, and NK cell cytotoxicity and alterations in T-cell function[31]. Depression-induced alteration in immunity caused by oral cancer differs from other cancers because it is not an indirect process but rather an effect caused by direct functional impairments and disfiguration. Together, these factors related to oral cancer indicate that the relationship between inflammation, depression, and immune surveillance is further amplified by microbial dysbiosis, localized exposure to carcinogens, and immense psychological implications.

Clinical significance of the triad

The clinical relevance of this triad lies in its potential to refine prognostic assessment, guide therapeutic decision-making, and expand the scope of patient management beyond conventional tumor-centric parameters. One of the most immediate applications is in risk stratification. Incorporating systemic inflammatory markers and validated depression assessment scales alongside TNM staging may improve prognostic accuracy. Patients with elevated inflammatory profiles and coexisting depressive symptoms may represent a biologically distinct subgroup with higher risk of rapid progression, treatment resistance, or recurrence[39]. This approach supports the development of composite prognostic models that integrate biological and psychosocial variables. In the context of treatment response, variability among patients with similar tumor characteristics remains a major clinical challenge. Differences in immune competence, influenced by systemic and psychological factors, may partially explain heterogeneous responses to radiotherapy, chemotherapy, and especially immunotherapy. Identifying patients with underlying immune dysregulation allows for treatment personalization, including closer monitoring, adaptive treatment protocols, or early integration of adjunctive therapies[40,41]. Another critical implication is in treatment tolerance and adherence. Depression is associated with reduced compliance, interruptions in therapy, and poorer engagement with follow-up care. Early identification and management of depressive symptoms may therefore indirectly improve oncologic outcomes by ensuring continuity and completion of planned treatment.

From a therapeutic standpoint, this framework opens avenues for adjunctive interventions. Anti-inflammatory strategies, behavioral interventions, and pharmacological management of depression may have a role not only in improving quality of life but also in modulating biological pathways relevant to tumor progression. This supports the concept of integrative oncology, where psychological and systemic factors are addressed alongside standard cancer treatment[42]. Finally, this perspective has implications for clinical research and trial design. Stratifying patients based on inflammatory and psychological profiles may improve interpretation of treatment outcomes and help identify subgroups that derive the greatest benefit from specific therapies. Overall, integrating these dimensions into clinical practice may enhance precision in prognosis, optimize therapeutic strategies, and contribute to more comprehensive care in oral cancer (Table 2).

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.

THERAPEUTIC PERSPECTIVES

The recognition of interconnected biological and psychological influences in oral cancer creates opportunities to expand therapeutic strategies beyond conventional oncologic treatment. Rather than viewing management as solely directed at tumor eradication, there is increasing rationale for interventions that also target systemic and host-related factors influencing disease behavior. One important area is the use of anti-inflammatory approaches as adjuncts to standard therapy. Pharmacological agents that modulate inflammatory pathways, including selective cytokine inhibitors and non-steroidal anti-inflammatory drugs, have been explored for their potential to alter tumor-promoting inflammation. Although not yet standard in oral cancer care, such strategies may be particularly relevant in patients demonstrating elevated systemic inflammatory markers[43].

Psychological and behavioral interventions represent another critical component. Structured approaches such as cognitive behavioral therapy, stress management, and supportive counseling have been shown to reduce depressive symptoms and may indirectly influence biological pathways linked to disease progression. Improving psychological well-being can enhance treatment adherence, functional recovery, and overall patient resilience during cancer therapy[44].

From a pharmacological perspective, certain antidepressant medications have demonstrated immunomodulatory and anti-inflammatory properties in addition to their primary neuropsychiatric effects[45]. While evidence in oral cancer remains limited, this raises the possibility of dual-benefit therapies that address both psychological and biological dimensions. The concept of integrative oncology becomes particularly relevant in this context. A multidisciplinary approach involving oncologists, mental health professionals, nutritionists, and rehabilitation specialists allows for comprehensive patient management. Such models aim to optimize not only survival outcomes but also functional status and quality of life. Emerging strategies may also include biomarker-guided interventions, where patients are stratified based on inflammatory or psychological profiles to receive tailored supportive therapies alongside standard treatment. This approach aligns with the broader movement toward precision medicine[46-48]. Overall, these therapeutic perspectives highlight the need to move beyond a purely tumor-focused model and adopt a more holistic framework that incorporates systemic and psychosocial dimensions into oral cancer care.

DISCUSSION

As demonstrated in this review, inflammation, depression, and immunity in oral cancer should be considered interconnected biological pathways rather than independent events. Within the context of the oral tumor microenvironment, persistent exposure to carcinogenic agents and microorganism products maintains a condition of low-grade inflammation, whereas depression provides an additional source of immune dysfunction. The overall consequence results in the creation of conditions whereby immune activity remains present but functionally compromised, hence allowing cancer cells to escape immune control. One major finding within this framework is the occurrence of “biological exhaustion,” whereby the inflammatory pattern within oral cancer bears remarkable resemblance to that of immune dysfunction witnessed in depression. At present, an important limitation in the literature is that these factors are often studied in isolation, with very few investigations evaluating inflammation, immune status, and psychological parameters together in the same patient cohorts. Therefore, this gap hinders our knowledge regarding how those processes work together in practice. Considering the existing data, we can assume that oral cancer progression is caused by a context-dependent interaction between the mentioned inflammatory response stimulated by carcinogens, immunomodulation by the oral microbiome, and alterations in neuroendocrine regulation associated with depressive symptoms. In this model, persistent inflammatory signaling coexists with impaired immune surveillance, resulting in a tumor-promoting environment despite ongoing immune activation.

This review is limited by its reliance on cross-sectional and observational studies, which restrict the ability to establish causal relationships between depression, inflammation, and immune alterations. Variability in study design, biomarker selection, and psychological assessment tools may also influence the consistency of interpretations. In addition, the dynamic nature of these interactions is not fully captured in the existing literature. Despite growing recognition of these factors, current evidence remains fragmented and largely extrapolated from broader oncological research. There is a clear need for oral cancer-specific longitudinal studies that simultaneously evaluate inflammatory markers, immune parameters, and psychological status within the same patient cohorts to help establish temporal relationships and clarify causality. Another important gap lies in the lack of standardized assessment frameworks; developing unified protocols that incorporate validated psychological scales alongside biological markers may improve reproducibility and facilitate translation into clinical practice. Future research should also focus on stratified and personalized approaches where integration of imaging-derived features with systemic biomarkers may allow for the development of predictive models that capture both tumor characteristics and host-related influences. From a therapeutic perspective, well-designed clinical trials are needed to evaluate whether targeted interventions, including anti-inflammatory agents, behavioral therapies, and pharmacological management of depression, can meaningfully influence oncologic outcomes in oral cancer.

CONCLUSION

In summary, oral cancer must be viewed not only from the local perspective but also as a systemic illness characterized by interactions through inflammatory and neuropsychological pathways. Oral cancer-related depression cannot be considered a mere psychological effect of the condition but rather represents a biological condition affecting the immune system, reducing antitumor immunity, and promoting tumor growth due to its contribution to systemic inflammation. A holistic clinical approach must be adopted in dealing with this problem. Identification and management of depression at early stages, combined with measures aimed at managing inflammation and immune disorders, could increase patient compliance, response to treatments, and even the disease course itself. Such treatments could include psychological and behavioral therapy as well as drug-based management for depression and other inflammation inhibitors. Adopting such a multidimensional framework may enhance prognostic precision, support personalized treatment strategies, and ultimately improve overall outcomes in patients with oral cancer.