Inflammation-driven carcinogenesis in oral cancer: A systematic review of cellular mechanisms and clinical perspectives

Abstract

Background and objectives

Oral squamous cell carcinoma (OSCC) represents the predominant form of oral cancer and remains a major cause of morbidity and mortality worldwide. Beyond traditional risk factors such as tobacco, alcohol, and betel quid consumption, mounting evidence implicates chronic inflammation as a driving force in oral carcinogenesis. This review synthesises current literature exploring how inflammatory mediators contribute to tumour initiation, progression, and clinical outcomes in OSCC.

Methods

A systematic search of PubMed, Scopus, Web of Science, Embase, and Cochrane Library databases was conducted according to PRISMA 2020 guidelines. Studies from 2020–2025 examining molecular and clinical interactions between inflammation and OSCC were analysed. Extracted data included inflammatory biomarkers, activated signalling pathways, and prognostic or therapeutic implications. The risk of bias was assessed using the Newcastle–Ottawa Scale and Cochrane RoB-2 tool. The review protocol was registered with PROSPERO (CRD420251141942).

Results

Forty-three eligible studies revealed that inflammatory cytokines such as TNF-α, IL-6, and IL-1β, together with chemokines like CXCL8, trigger oncogenic cascades involving NF-κB and STAT3, leading to enhanced proliferation, angiogenesis, and epithelial–mesenchymal transition. Oxidative DNA damage and immune suppression mediated by M2 macrophages and PD-1/PD-L1 signalling further facilitate tumour aggressiveness. Elevated COX-2, STAT3, and systemic inflammatory ratios were strongly associated with poor prognosis.

Interpretation and conclusions

Persistent inflammation acts as a critical determinant in OSCC pathogenesis. Integrating inflammation-related biomarkers and anti-inflammatory therapeutic strategies may improve early detection, prognostication, and patient survival outcomes.

Oral cancer remains a major global health concern, with oral squamous cell carcinoma (OSCC) constituting over 90% of malignancies arising in the oral cavity.¹ Despite improvements in diagnostic and treatment strategies, global mortality rates remain high, primarily due to late-stage detection and limited therapeutic success in advanced disease.² The burden of OSCC varies geographically and is closely tied to established risk factors such as tobacco use, alcohol consumption, and high-risk human papillomavirus (HPV) infection. In regions of South and Southeast Asia, betel quid chewing further elevates disease incidence.³

Beyond direct carcinogenic injury, these risk factors exert profound effects through chronic inflammation, an established contributor to nearly 15% of human cancers and often described as the ‘seventh hallmark of cancer. Persistent inflammatory conditions including oral lichen planus and chronic periodontitis create a microenvironment favourable for malignant transformation.⁴ This state is characterised by sustained immune cell activity and continuous release of cytokines, chemokines, growth factors, and reactive oxygen species (ROS), which promote DNA damage, angiogenesis, tumour invasion, and immune evasion.⁵

Given these interconnected mechanisms, this systematic review synthesises current evidence to clarify how inflammation drives OSCC development and to highlight its implications for diagnosis, prognosis, and emerging therapeutic strategies.

Methods

This systematic review followed the PRISMA 2020 guidelines. while elements of the Arksey and O’Malley framework supported the initial scoping and literature mapping. The review process comprised five stages: defining the research question, identifying relevant studies, screening based on predefined eligibility criteria, extracting data, and synthesising the findings. The protocol was registered in PROSPERO (CRD420251141942) to ensure transparency and methodological rigor. Independent reviewers conducted study selection, data extraction, and risk-of-bias assessment, with discrepancies resolved through consensus. Study selection, data extraction, and risk of bias assessment were carried out independently by reviewers, with any disagreements resolved through discussion and consensus.

Eligibility criteria

This review included studies that explored mechanistic or clinical links between chronic inflammation and oral cancer, with emphasis on OSCC. Eligible articles comprised original research, including observational designs, experimental studies, and clinical trials. Studies involving human participants, human-derived cell lines, or animal models with direct translational relevance were included. Only English-language publications were considered. Studies were excluded if they were non-English, secondary reviews without primary data, case reports, editorials, commentaries, conference abstracts, or investigations limited solely to animal models without human applicability.

Information sources and search strategy

A comprehensive search of PubMed, Scopus, and Web of Science used MeSH terms and free-text keywords related to oral cancer, inflammation, cytokines, oxidative stress, and key signalling pathways. Reference lists were manually screened.

Data extraction

A structured data extraction sheet was developed and piloted prior to full extraction. Information collected from each study included the first author’s name, year of publication, country, study design, sample size, characteristics of the study population, specific inflammatory pathways or biomarkers investigated, principal mechanistic findings, and reported clinical implications such as diagnostic, prognostic, or therapeutic outcomes. Two reviewers independently extracted the data to minimise bias, and any inconsistencies were resolved by consensus.

Risk of bias assessment

The methodological quality of the included studies was appraised independently by two reviewers (MR and DK). For observational studies, the Newcastle–Ottawa Scale (NOS) was applied, whereas clinical trials were evaluated using the Cochrane Risk-of-Bias tool. Preclinical and mechanistic studies were assessed using tailored checklists, focusing on aspects such as clear definition of controls, reproducibility of methods, blinding, and appropriate statistical analyses. The results of the bias assessment were considered during data synthesis and interpretation to ensure that conclusions were informed by the strength and reliability of the available evidence.

Results

The systematic search and screening process from 1,260 records identified through database searching, a total of 43 studies^6-49 met the inclusion criteria and were included in the final analysis. yielded 43 studies detailing the multifaceted role of inflammation in OSCC ( Fig. 1). Details of primary studies (2020-2025) evaluating inflammation–related markers are listed in Table I^50-54. Observational studies are listed in Table II^50-52,54. Risk of bias assessment is provided in Figure 2 and Figure 3 (for clinical trials). The findings were synthesised and organised into seven key thematic areas, reflecting the core mechanisms by which inflammation drives carcinogenesis.

Fig. 1.

PRISMA 2020 flow diagram depicting the study selection process for the systematic review, including identification, screening, eligibility assessment, and final inclusion of studies.

Table I.

Demographic and design characteristics of primary studies (2020–2025) evaluating inflammation-related markers in OSCC. The table lists author/year, country, study outline/design, total participants (n), age (reported as mean±SD or median with spread as available), diagnostic confirmation (histopathology unless stated), and timing of assessment (e.g., pre-treatment, peri-operative, post-therapy follow up)

Author (yr)	Country	Research outline	Total participants, n	Age (yr), mean (SD)	Diagnosis	Time of assessment
Ruiz-Ranz et al50, 2022	Spain	Large single-centre cohort evaluating pre-operative systemic inflammatory markers (NLR, PLR, MLR, SII) and correlating them with tumour-infiltrating immune cells; outcomes = OS/DFS.	348	∼62 yr (reported as mean/median;SD NR)	OSCC (surgery cohort)	Pre-operative peripheral blood before radical surgery.
Cho et al51, 2022	South Korea	Retrospective surgical cohort assessing several hematologic markers; PLR identified as independent prognostic marker for OS/DFS.	269	55.1±15.2	OSCC (resection)	“Within one month before surgery.”
Zakaria et al52, 2022	Malaysia	Stepwise Cox models using both pre- and post-treatment markers (LMR, SII, PLR, PLC) to predict OS/DFS.	151	59.70±13.87 yr	OSCC (mixed stages)	Pre-treatment labs within 1 week of therapy start; post-treatment ≥1 week after surgery/radiotherapy and ≥2 weeks after chemotherapy.
Zhu et al53, 2024	China	Trial-based analysis showing derived neutrophil-to-lymphocyte ratio (dNLR) predicts prognosis and benefit from TPF induction chemotherapy in locally advanced OSCC.	224	55.4 yr (median; range 26–75) (mean/SD NR)	Locally advanced OSCC (stage III/IVA)	Baseline (trial enrolment) before treatment; dNLR from pre-treatment CBC.
Nicoară et al54, 2024	Romania	Retrospective cohort tracking SII and NLR across treatment phases (pre-/post-surgery; pre-/post-adjuvant radiotherapy).	154	62.3±10.1 yr	OSCC (surgery; subset with adjuvant RT)	Pre-surgery; pre-first RT session; post-last RT session.

OSCC, oral squamous cell carcinoma; RT, radiotherapy; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; SII, systemic immune-inflammation index; PNI, prognostic nutritional index; IHC, immunohistochemistry; Dx/Prog, diagnosis/prognosis

Table II.

Methodological quality characteristics of observational studies in oral squamous cell carcinoma (OSCC), assessed using Newcastle–Ottawa Scale (NOS) domains including selection, comparability, outcome ascertainment, follow-up, and overall risk of bias

Study	Selection (representativeness, inclusion)	Comparability (confounding control)	Outcome ascertainment (definition/measurement)	Follow up and missing data	Overall (NOS-based)
Ruiz-Ranz et al50, 2022	Low–moderate: single-centre surgical cohort	Moderate: multivariable models likely; residual confounding plausible	Low: histopathology + routine labs; OS/DFS standard	Low–moderate: clinical follow-up typical; missingness not fully detailed	Moderate risk
Cho et al51, 2022	Low–moderate: resection cohort, consecutive series implied	Moderate: adjusted analyses reported; selection bias possible	Low: pre-op labs within set window; hard clinical endpoints	Low–moderate: pre-op timing well defined; attrition unclear	Moderate risk
Zakaria et al52, 2022	Moderate: mixed-stage cohort, stepwise modelling	Moderate: pre/post markers modelled; confounding from treatment pathways possible	Low: standard haematology indices; OS/DFS registry/records	Moderate: timing windows defined; post-treatment sampling variability	Moderate risk
Nicoară et al54, 2024	Moderate: retrospective, treatment-phase subsets	Moderate: phase-specific comparisons; residual confounding likely	Low: CBC-derived indices, reproducible measures	Moderate: multiple time points; missingness handling variably reported	Moderate risk

Key drivers: non-random allocation, single-centre designs, incomplete reporting of missing data

Mitigations: objective outcomes, histologic confirmation, standardized laboratory indices

Fig. 2.

Risk of bias summary of included randomised controlled/clinical trials. The condensed results explain that chronic inflammation in OSCC operates through interconnected biological mechanisms in 7 steps.

Fig. 3.

Risk of bias summary across methodological domains, showing the percentage distribution of low (blue), unclear (black), and high (dark grey) risk of bias among the included studies.

Cytokines and chemokines

The master conductors of the inflammatory orchestra

Cytokines and chemokines act as central regulators of the inflammatory tumour microenvironment in OSCC, where their sustained activation supports tumour initiation and progression. Persistent elevation of pro-inflammatory cytokines is a defining feature of the OSCC microenvironment.

Tumour necrosis factor-alpha (TNF-α) is expressed by both malignant cells and surrounding stromal and inflammatory components.⁶ It signalling promotes cancer cell proliferation, invasion, and angiogenesis primarily through continuous activation of the NF-κB pathway.⁷ This activation enhances the expression of anti-apoptotic and survival genes, enabling tumour cells to evade programmed cell death. Importantly, increased TNF-α signalling has been observed in oral potentially malignant disorders that later progress to OSCC, indicating its role in early malignant transformation.⁸

Interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) further reinforce inflammatory signalling. IL-6 activates the STAT3 pathway, contributing to tumour growth, metastasis, and therapy resistance. IL-1β promotes nitric oxide production and sustains a carcinogenic microenvironment,⁹ while autocrine IL-1 signalling within OSCC cells maintains NF-κB activation.

Among chemokines, CXCL8/IL-8 plays a critical role. Predominantly produced by tumour-associated macrophages, CXCL8 enhances OSCC cell motility, invasion, and angiogenesis. Reciprocal interactions between tumour cells and macrophages amplify CXCL8 production, creating a feedback loop that drives metastatic progression.¹⁰

Oxidative stress and DNA damage: The genesis of malignancy

Oxidative stress is a central mechanism linking chronic inflammation to carcinogenesis in OSCC. Persistent inflammatory activity disrupts the balance between reactive oxygen species (ROS) generation and antioxidant defences, creating a pro-mutagenic environment.¹¹ Activated neutrophils and macrophages release excessive ROS and reactive nitrogen species, which are further amplified by external carcinogens such as tobacco and alcohol.¹²

Sustained oxidative stress directly damages cellular macromolecules, particularly DNA, leading to strand breaks, base modifications, and genomic instability. Among oxidative DNA lesions, 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a key biomarker and mutagenic intermediate. Elevated 8-OHdG expression has been consistently demonstrated in OSCC tissues and reflects widespread oxidative DNA damage.^13,14

This lesion promotes G-to-T transversion mutations, a common genetic alteration in human cancer.¹⁵ Clinically, nuclear localisation of 8-OHdG is associated with aggressive disease and reduced survival, underscoring its prognostic significance.¹⁶ These findings illustrate a self-perpetuating cycle in which inflammation-induced oxidative stress drives malignant transformation and tumour progression.

Proliferation and cell survival pathways: Fuelling uncontrolled growth

Chronic inflammatory signalling in OSCC converges on key intracellular pathways that regulate cell proliferation, survival, and apoptosis. Persistent activation of these pathways by the inflammatory tumour microenvironment disrupts normal cellular regulation and supports malignant growth.

The NF-κB pathway functions as a central mediator linking inflammation to oncogenesis. While NF-κB activation is transient and tightly regulated in normal cells, OSCC is characterised by its constitutive activation, leading to increased expression of genes involved in cell cycle progression, survival, and invasion, including cyclin D1 and anti-apoptotic proteins¹⁷ This sustained signalling is driven by inflammatory cytokines such as TNF-α and IL-1β, as well as exposure to tobacco-related carcinogens, directly connecting etiological factors with tumour-promoting pathways¹⁸ Notably, NF-κB subunit predominance differs by tumour aetiology, with p65 associated with HPV-positive tumours and p50 linked to more aggressive HPV-negative OSCC.¹⁹

STAT3 is another critical oncogenic pathway frequently overexpressed and persistently activated in OSCC.²⁰ Primarily induced by IL-6, STAT3 promotes proliferation, angiogenesis, immune suppression, and resistance to apoptosis, supporting sustained tumour survival.²¹

The COX-2/PGE₂ axis further contributes to tumour progression. COX-2 overexpression is evident in premalignant and malignant oral lesions, while elevated PGE₂ enhances migration, angiogenesis, and immune evasion. High COX-2 expression correlates with recurrence and poor survival, underscoring its prognostic and therapeutic relevance.²²

Angiogenesis and tumour growth: Building the supply lines

For a tumour to grow beyond a few millimetres in size, it must secure its own blood supply through the process of angiogenesis. The inflammatory tumour microenvironment is a potent instigator of this process, with the hypoxia-HIF-1α-VEGF axis being the central mechanism²³.

The rapid proliferation of cancer cells creates a hypoxic (low oxygen) core within the tumour. This hypoxia is a powerful stimulus for the stabilisation hypoxia-inducible factor-1α (HIF-1α), a master transcription factor that orchestrates the cellular response to low oxygen. Studies confirm that HIF-1α is highly expressed in OSCC, particularly in the hypoxic tumour center.²⁴ Once stabilised, HIF-1α activates the transcription of numerous genes, most notably vascular endothelial growth factor (VEGF).²⁵ VEGF is the most critical pro-angiogenic factor in OSCC. It stimulates the proliferation, migration, and differentiation of endothelial cells, leading to the formation of new blood vessels. This neo vasculature provides tumours with essential nutrients and oxygen and also serves as a conduit for metastasis.²⁶ High VEGF expression in OSCC is consistently associated with increased microvascular density, tumour aggressiveness, and poor patient prognosis. A meta-analysis found that VEGF overexpression was correlated with an 88% increased risk of death.²⁷

The inflammatory tumour microenvironment fuels this entire process. Inflammatory cells release a cocktail of cytokines and growth factors that directly or indirectly promote angiogenesis.²⁸ For example, inflammatory signalling through STAT3 can directly increase VEGF production, creating a vicious cycle where inflammation drives hypoxia and angiogenesis, and the leaky new vessels facilitate further infiltration of inflammatory cells, perpetuating the pro-tumourigenic state²⁹.

Epithelial–mesenchymal transition (EMT) and metastasis: Enabling the escape

Metastasis is the leading cause of cancer-related mortality, and its initiation in OSCC is closely linked to epithelial-mesenchymal transition (EMT). During EMT, epithelial tumour cells lose cell–cell adhesion and acquire migratory and invasive properties, facilitating early metastatic spread.³⁰ The inflammatory tumour microenvironment plays a critical role in driving this process.

Transforming growth factor-beta (TGF-β) is a dominant inducer of EMT in OSCC, promoting transcriptional repression of epithelial markers such as E-cadherin while enhancing mesenchymal markers including vimentin. Pro-inflammatory cytokines, particularly TNF-α, further reinforce EMT through activation of stress-related signalling pathways.³¹

Invasion is enabled by extracellular matrix degradation mediated by matrix metalloproteinases (MMPs). MMP-2 and MMP-9 are consistently overexpressed in OSCC and are concentrated at invasive tumour margins. Their expression correlates strongly with depth of invasion and lymph node metastasis, serving as adverse prognostic indicators. Mechanistically, NF-κB signalling links inflammation to EMT by inducing transcription factors such as Snail and Slug, thereby directly enhancing metastatic potential.³²

Tumour microenvironment and immune evasion: disarming the guards

A fundamental requirement for tumour survival and progression is the ability to evade destruction by the host’s immune system. The chronic inflammatory TME in OSCC is paradoxically characterised by profound immunosuppression, orchestrated by a specific cast of immune cells^33,34

Tumour-associated macrophages (TAMs) are a major component of the immune infiltrate. While M1-polarised macrophages can have anti-tumour functions, the OSCC TME is skewed towards the pro-tumourigenic M2 phenotype. M2 TAMs actively suppress anti-tumour immunity by releasing immunosuppressive cytokines like IL-10 and TGF-β, promote angiogenesis, and remodel the ECM to facilitate invasion.³⁵ The density of M2 TAMs in the TME is a strong predictor of poor prognosis in OSCC patients.

Regulatory T cells (Tregs) are another critical immunosuppressive population. These cells are significantly enriched within OSCC tumours and are potent suppressors of effector T cells, particularly the CD8+ cytotoxic T lymphocytes that are essential for killing cancer cells.³⁶ Tregs in the TME also undergo metabolic reprogramming to adapt to the harsh, nutrient-poor conditions, ensuring their survival and sustained suppressive function.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that expand during cancer and are powerful inhibitors of T-cell responses.³⁷ Myeloid-derived suppressor cells expand in OSCC, correlating with advanced stage, and suppress T-cell function through arginase-1–mediated amino acid depletion and reactive oxygen species production.

Together, TAMs, Tregs, and MDSCs create a formidable immunosuppressive barrier that allows the tumour to grow unchecked. This immune evasion is often mediated by immune checkpoint pathways, such as the interaction between programmed cell death protein-1 (PD-1) on T cells and its ligand (PD-L1) on tumour cells and immune cells, which leads to T-cell exhaustion.³⁸

Clinical perspectives: From bench to bedside

The deep understanding of inflammation’s role in OSCC has direct and significant clinical applications, spanning prognosis and therapy.³⁹

Systemic inflammatory markers

Simple blood-based markers like the neutrophil-to-lymphocyte ratio (NLR) have emerged as powerful, cost-effective prognostic tools. An elevated preoperative NLR is significantly associated with lymph node metastasis and worse overall and progression-free survival in OSCC patients, establishing it as an independent prognostic factor.⁴⁰

Tumour-specific markers

Within the tumour tissue, the expression of inflammatory molecules is highly prognostic. High expression of COX-2 is a robust negative prognostic marker, strongly associated with tumour recurrence and decreased survival. Similarly, the constitutive activation of STAT3 is consistently linked to poor clinical outcomes in OSCC.⁴¹

Therapeutic targets

The centrality of inflammation to carcinogenesis makes its pathways prime targets for intervention. The STAT3 pathway is a major therapeutic target. Inhibiting STAT3 not only has the potential to halt tumour proliferation directly but also to dismantle the immunosuppressive TME, which could synergise with other treatments.⁴² Immune checkpoint inhibitors, including pembrolizumab and nivolumab, target PD-1/PD-L1 signalling, restoring T-cell activity and significantly improving survival in advanced OSCC patients.^43-44

Across the included studies, observational cohorts generally showed moderate risk of bias, driven mainly by confounding and retrospective selection. Objective outcomes (OS/DFS) and standardised laboratory measures (e.g., NLR, SII) supported low risk in outcome measurement. The trial-based analysis showed some concerns due to its post-hoc nature (predictive use of dNLR within a randomised dataset), despite otherwise low risks in randomisation and outcome assessment Table III.³²

Table III.

Risk of bias assessment of trial-based study in OSCC using Cochrane RoB-2 domains and overall judgment

Study	Randomisation process	Deviations from intended interventions	Missing outcome data	Measurement of the outcome	Selection of the reported result	Overall (RoB-2)
Dong et al 32, 2025	Low risk: phase III randomized backbone	Low risk: protocolized induction/standard care	Low risk: survival outcomes customary in RCT follow-up	Low risk: objective survival endpoints	Some concerns: post-hoc prognostic use of dNLR/cut-off selection may risk selective reporting	Some concerns

Although embedded in a randomized trial, the exposure of interest (dNLR) is observational/prognostic, not randomized; hence the ‘some concerns’ judgment for selective reporting

Discussion

This systematic review demonstrates that chronic inflammation is not merely a by-product of OSCC but a critical driver of its initiation, promotion, and progression. Across clinical, experimental, and molecular studies, the evidence strongly indicates that inflammatory mediators shape multiple hallmarks of tumour biology, supporting earlier claims that inflammation represents a functional engine of carcinogenesis. The convergence of cytokine signalling, oxidative stress, proliferative pathways, angiogenesis, EMT, and immune suppression collectively sustains an oncogenic microenvironment, underscoring inflammation’s central role in OSCC pathophysiology.

Cytokines such as TNF-α, IL-6, and IL-1β emerged as key regulators of tumour-promoting pathways. TNF-α persistently activated NF-κB, enhancing cell survival and resistance to apoptosis. IL-6-mediated STAT3 activation strongly associated with poor prognosis and treatment resistance was consistently elevated in OSCC.⁴⁴ IL-1β contributed to nitric oxide production and chronic mucosal injury, maintaining a tumour-supportive inflammatory state. Chemokines, especially CXCL8/IL-8 released by tumour-associated macrophages, further promoted invasion and angiogenesis while establishing feedback loops that reinforced metastatic potential.

Oxidative stress acted synergistically with inflammatory signals. Elevated ROS/RNS levels contributed to DNA damage, with increased 8-OHdG expression correlating with aggressive disease and reduced survival. This interaction was intensified by external carcinogens such as tobacco and alcohol. Oxidative DNA lesions, including G-to-T mutations, supported genomic instability, a known accelerator of carcinogenesis.⁴⁵

Proliferative and survival pathways were predominantly mediated by NF-κB, STAT3, and COX-2/PGE₂ signalling. NF-κB promoted cyclin D1 expression and survival gene activation. while STAT3 supported angiogenesis and immunosuppression.⁴⁶ COX-2 overexpression, linked with recurrence and poor prognosis contributed to enhanced motility and immunomodulation.

Angiogenesis was strongly associated with hypoxia-driven HIF-1α-VEGF signalling, with VEGF expression correlating with tumour aggressiveness and poor survival. STAT3 further amplified VEGF production,⁴⁷ illustrating a convergence between inflammatory and hypoxic cues.

Metastatic progression was supported by EMT, driven by TGF-β, TNF-α, and NF- κB. Upregulation of MMP-2 and MMP-9 correlated with invasion depth and nodal metastasis.⁴⁸ Within the tumour microenvironment, immunosuppressive cell populations including M2 macrophages, Tregs, and MDSCs suppressed antitumour immunity. PD-1/PD-L1-mediated T-cell exhaustion further facilitated immune escape, explaining the clinical benefit of checkpoint inhibitors in OSCC. Prognostically, systemic inflammatory indices (NLR, PLR, LMR, SII) consistently predicted adverse outcomes. while tissue markers such as COX-2 and phospho-STAT3 strengthened risk stratification.⁴⁹ Collectively, these findings reinforce chronic inflammation as a foundational mechanism in OSCC and highlight the potential of inflammation-focused biomarkers and targeted therapies to improve clinical management.

Although this review provides strong mechanistic insights, several limitations must be acknowledged. Most included observational studies were retrospective and single-centre, carrying moderate risk of bias due to confounding and incomplete reporting. Substantial heterogeneity in biomarker definitions and cut-off values limited direct comparability across studies. In addition, the trial-based assessment of derived NLR was post-hoc, introducing potential selective reporting bias.⁵⁵ The scarcity of longitudinal studies tracking inflammatory changes in high-risk populations further restricted causal inference.

Future research should prioritise large prospective cohorts to validate systemic inflammatory indices (NLR, PLR, SII) and tissue biomarkers such as COX-2 and STAT3. Randomised trials evaluating STAT3, COX-2, and NF-κB inhibitors, alone or in combination with immunotherapy, are needed. Integrating personalised inflammatory signatures and multi-omics approaches may further refine risk stratification and therapeutic decision-making.

Overall, the results of this systematic review provide compelling evidence that chronic inflammation is an indispensable driver of OSCC pathogenesis. It initiates DNA damage, fuels proliferation, sustains angiogenesis, induces EMT, and orchestrates immune evasion. Clinically, systemic inflammatory indices and tissue biomarkers are reliable prognostic tools, while therapeutic strategies targeting STAT3, COX-2, NF-κB, and PD-1/PD-L1 are already transforming management.

Author contributions

MR: Conceptualisation, supervision, and critical review; AK: Data curation, analysis, manuscript writing; DK: Methodology, manuscript writing.

Financial support and sponsorship

None.

Conflicts of Interest

None.

Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation

The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.