Introduction

Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers, and it predominantly occurs in developing nations [1]. The origin of OSCC is the squamous epithelial cells lining the oral cavity, which include the tongue, lips, buccal mucosa, floor of the mouth, hard palate, and oropharynx. It is known due to its aggressive nature, tendency for local invasion, and high metastasis rate to regional lymph nodes, which significantly contribute to its morbidity and mortality [2]. With a higher frequency seen in underdeveloped nations, OSCC is the sixth most frequent cancer worldwide. Key risk factors include the use of smokeless and smoking tobacco, alcohol consumption beyond the permissible limits, betel nut chewing, and human papilloma virus (HPV) infection, particularly HPV-16 [3]. Contributing factors also include genetic predispositions, poor oral hygiene, and chronic irritation or trauma to the oral mucosa. The frequency of OSCC is much higher in males than in females, which may be due to the fact of more hazardous behavioral practices and risk factors among men. A series of genetic mutations and epigenetic changes contribute to the pathophysiology of OSCC, converting normal oral epithelial cells into cancerous cells. The main molecular pathways involved in OSCC comprise the p53 tumor suppressor pathway, the retinoblastoma (Rb) pathway, and a few signaling cascades like EGFR, MAPK, and PI3K/AKT [3, 4]. The changes result in losing the normal checks that limit the growth of cells, developing cell resistance to programmed cell death (apoptosis), supplying tumor tissue with new blood vessels, and enhancing the ability to invade other tissues [3].

Programmed death-ligand 1 (PD-L1), also known as B7-H1, together with its receptor (PD-1), are key element of the immune checkpoint pathway, which plays a significant role in regulating immune responses [5]. Under physiological conditions, this pathway is essential for maintaining immune homeostasis and preventing autoimmunity by inhibiting T-cell activity [6]. However, the tumor cells exploit such a machinery by PD-L1 overexpression, which leads to the suppression of the cytotoxic T-cell responses, thereby allowing an unfettered tumor progression. Although extensive research has been done to determine whether the expression levels of PD-1 and PD-L1 proteins in tumor tissues correspond with the biological behavior and clinical features of head and neck squamous cell carcinoma (HNSCC), their precise role and clinical relevance in OSCC remain ambiguous [7]. In OSCC, tumor cell-expressed PD-L1 interacts with PD-1 receptors on T cells to deliver inhibitory signals that lead to the reduction in T-cell proliferation, cytokine secretion, and cytotoxic activity. This immune checkpoint interaction facilitates tumor immune evasion, making PD-1/PD-L1 blockade a promising therapeutic strategy [8]. Nivolumab and pembrolizumab, two well-known PD-1 inhibitors, have been approved by the FDA to treat a number of malignancies, including HNSCC, which includes OSCC [9].

In addition to PD-1 inhibitors, several PD-L1 inhibitors (PD-L1-I), such as durvalumab and atezolizumab, are undergoing clinical trials to assess their efficacy in treating HNSCC and other cancers. These treatments have been extremely effective in shrinking tumors and in achieving the remission phase, thus representing a significant leap in cancer immunotherapy. The clinical application of PD-L1-I in OSCC represents a major advancement in its management. Clinical trials such as CheckMate141 and KEYNOTE-012 have shown that these inhibitors can improve overall survival (OS) and reduce adverse effects compared to standard therapies [10].

In summary, the integration of PD-L1-I into the treatment paradigm for OSCC signifies a major advancement in cancer immunotherapy, providing new avenues for effective and targeted treatment [9, 11]. Several systematic reviews have published findings on PD-L1 expression in OSCC, however, a thorough integrative analysis that covers its expression, prognostic implications, and correlation with disease progression is still lacking. The present review is committed to mend this significant gap by consolidating the current evidence base, identifying variances among different research studies, and providing potential suggestions for future research direction.

Materials and methods

Results

Prisma flow chart

A total of 22 systematic reviews were obtained during the initial search. After complete screening, a total of 6 articles were reviewed (Figure 1).

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Figure 1. PRISMA 2020 flow diagram showcasing systematic reviews included from searches of databases and registers only. PRISMA flow chart displaying the review process, detailing the number of records identified, screened, excluded, and included in the final analysis. Adapted from “PRISMA” (http://www.prisma-statement.org/). Accessed June 25, 2024. © 2024–2025 the PRISMA Executive. Distributed under a Creative Commons Attribution (CC BY 4.0) license.

Discussion

The greater PD-L1 expression in females suffering from OSCC might be the consequence of different biological and genetic factors. Hormones, and more specifically the influence of estrogen, are likely to play a major role. Estrogen acts as an immune modulator; therefore, it may increase the PD-L1 expression significantly. Furthermore, genetic differences, including several variations in the immune-related genes and X-chromosome linked factors, might contribute to the increased PD-L1 expression in females. Overall, these hormonal influences, along with genetic factors, can affect the internal tumor microenvironment, leading to a higher prevalence of PD-L1 overexpression in female patients.

Although higher PD-L1 expression is predominant in female OSCC patients according to multiple studies, the significance of this finding for clinical purposes is inconclusive. Elevated PD-L1 levels may reflect sex-specific immunoregulatory mechanisms, potentially influenced by estrogen signaling, which has been shown to upregulate PD-L1 expression in various cancers. While the clinical significance remains to be fully established, these findings may have implications for tailoring immunotherapeutic strategies, as gender-specific immune responses could influence treatment outcomes in OSCC. Yet, the current studies fail to find a consistent link between this manner of expression and the way OS, progression of the disease or response to immunotherapy vary in females as compared to males. Further studies are needed to validate the influence of sex-based PD-L1 expression on clinical outcomes or allocation of particular treatments [18–21].

Numerous underlying mechanisms attribute to the differential PD-L1 expression between smokers and non-smokers as well as between drinkers and non-drinkers. Smoking leads to alterations in the tumor microenvironment owing to its contribution to chronic inflammation and oxidative stress. This microenvironment might trigger immune escape of tumor cells, which results in the suppression of PD-L1 expression to evade detection by the immune system. Additionally, the carcinogens present in tobacco can cause genetic mutations and epigenetic changes, affecting the regulatory pathways of PD-L1 expression. In contrast, non-smokers may have a different inflammatory and immune landscape, leading to higher PD-L1 expression as part of their immune response to tumor presence [21].

Alcohol consumption downregulates immune responses by altering cytokine production. This immunosuppression might result in lower PD-L1 expression in drinkers due to a less active immune surveillance mechanism. Individuals who abstain from alcohol may show higher PD-L1 expression due to a more preserved and responsive immune system. This enhanced immune activity may trigger upregulation of PD-L1 as a feedback mechanism to regulate immune responses [22].

Both smoking and alcohol consumption cause chronic systemic changes affecting overall immune function and the tumor microenvironment. These lifestyle factors could influence not only the direct regulation of PD-L1 but also other immune checkpoints and pathways interacting with PD-L1 expression. The heterogeneity in study findings suggests that individual variations in genetics, environment, and the complex interplay of multiple factors lead to differences in PD-L1 expression patterns among smokers, non-smokers, drinkers, and non-drinkers [23].

The association involving PD-L1 expression and staging of the tumor, along with grading, can be explained by the interactions between tumor biology and immune evasion mechanisms. Poorly and moderately differentiated tumors are more likely to exhibit higher PD-L1 expression compared to well-differentiated tumors. This might be due to the more aggressive nature of poorly differentiated tumors, which often develop mechanisms to escape immune surveillance, including upregulating PD-L1 to inhibit T-cell activity. High PD-L1 expression in these tumors helps them avoid destruction by the immune system, facilitating tumor growth and metastasis [24].

Positive PD-L1 expression has been significantly linked to advanced clinical features such as lymph node involvement, distant metastasis, and higher TNM stages. Advanced-stage tumors often upregulate PD-L1 to enhance immune evasion. This allows them to suppress antitumor immunity, particularly at metastatic sites where the immune cell activities are more pronounced [25].

The different levels of PD-L1 expression in relation to tumor stages and grades indicate its potential as a prognostic marker to detect tumor aggressiveness. In addition to this, it points to the importance of PD-L1 as a candidate marker for immunotherapy, especially for patients who are in the later stages of the disease [26].

The lack of significant association between PD-L1 expression and survival outcomes, including OS, DFS, and DSS, across multiple studies suggests a variation between PD-L1 and tumor biology [26].

This evidence implies that merely considering PD-L1 expression as a predictor in HNSCC might be insufficient. Other parameters, including tumor heterogeneity, immune microenvironment, and treatment modalities, probably have a greater impact on patient outcomes. Additionally, the high heterogeneity observed among studies underscores the necessity for standardized approaches and extensive, rigorously controlled investigations to validate the prognostic utility of PD-L1 expression in HNSCC [27, 28].

Overall, PD-L1 is still a viable target to counteract the immune system’s resistance in HNSCC, although its use as a prediction marker concerning the survival of patients seems to be quite insignificant according to the available data. Additional studies are needed to specify the association between the expression of PD-L1 in patients and their prognosis, thus opening up new treatment options for OSCC and other types of tumors [29].

The finding of an association between HPV infection and PD-L1 expression in OSCC may signify that there is a link between viral etiology and immune checkpoint activation. The evidence base indicates that PD-L1 positivity among HPV-positive OSCC patients is higher, giving rise to the hypothesis that HPV is instrumental in the immune microenvironment. HPV infection-driven alterations in the tumor microenvironment may lead to the upregulation of PD-L1 as a mechanism by which cells escape immune surveillance [30]. HPV infection-driven changes within the tumor microenvironment may favor upregulation of PD-L1 as part of an immune surveillance escape mechanism. This increase in PD-L1 expression constitutes the creation of an immunosuppressive environment, enabling tumor cells to escape from immune detection and eradication. Despite the association of HPV infection with PD-L1 expression, however, the role of PD-L1 as a prognostic marker in HPV-positive OSCC is uncertain, with a need for further mechanistic and clinical investigation regarding this relationship. The predictive value of PD-L1 expression in HPV-positive OSCC is still undetermined. Therefore, while there are comparable OS rates with their HPV-negative counterparts, PD-L1 expression can influence PFS. Nevertheless, data on low PD-L1 expression and survival outcomes according to HPV status are still scant. The findings indicate the complicated interplay of HPV infection, expression of PD-L1, and the patient’s prognosis in OSCC. This warrants further investigations in order to fully understand the clinical implications and therapeutic potential of these factors [31].

PD-L1, present on both the malignant as well as the immune cells, engages with its counterpart receptor PD-1 on TILs, leading to T-cell exhaustion or anergy. The binding of PD-L1 with PD-1 on TILs hampers T-cell activation and T-cell function regimen allowing cancer cells to remain undetected by the immune system and evade destruction [32].

Tumors with high density of immune cell infiltration display increased PD-L1 expression levels, and this may be seen as an ‘aggressive’ immune response against the tumor. The tumor microenvironment’s CD8+ cytotoxic T lymphocytes (CTLs) are evidence that the immune system is making an effort to detect and kill cancer cells. In this case, the production of PD-L1 might serve as a counter-regulatory mechanism to control the magnitude of the immune response and avoid causing undue tissue damage [32, 33].

On the contrary, in instances where CD8+ TIL count is low, PD-L1 expression may still assist the tumors in evading the immune system by suppressing the cytotoxic activity of the T cells. This leads to an immunosuppressive microenvironment that, in turn, promotes tumor progression and metastasis. Furthermore, PD-1-positive TILs reflect a condition of T-cell exhaustion due to continuous exposure to antigens, leading to functional impairment and loss of anti-tumor activity [34].

As a whole, the association of PD-L1 expression with TIL density reflects the dynamic balance between anti-tumor immunity and immune evasion within the tumor microenvironment (Figure 2) [35].

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Figure 2. Interrelationship of PD-L1 expression and TILs in immunoregulation and immunotherapy. It presents a streamlined cellular pathway flowchart that elucidates the intricate mechanism underlying PD-L1 expression and the interaction with TILs within the tumor microenvironment. This diagram is structured to illustrate the sequential and interrelated biological processes that contribute to the immune evasion tactics employed by tumors. PD-L1: programmed death-ligand 1; PD-1: programmed death-1; TILs: tumor infiltrating lymphocytes.

Treatment strategies involving PD-L1-I have shown promise in improving patient outcomes (Figure 3). OSCC is characterized by its aggressive nature and resistance to conventional therapies, making immunotherapy an appealing alternative. Clinical trials have been conducted to test the effectiveness of PD-L1-I, such as pembrolizumab and nivolumab, in treating OSCC [36].

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Figure 3. Immune checkpoint pathway and clinical implications in OSCC. This flowchart illustrates the mechanism of PD-L1 receptor expression in OSCC cells and its interaction with PD-1 on T cells, leading to immune evasion. It details the sequence from antigen presentation by OSCC cells, T cell activation, and the subsequent inhibitory signal transduction that results in T cell exhaustion. Clinical implications include the consideration of immune checkpoint inhibitors targeting the PD-L1/PD-1 interaction to evaluate immunotherapy response. PD-L1: programmed death-ligand 1; PD-1: programmed death-1; OSCC: oral squamous cell carcinoma.

One approach involves utilizing PD-L1 inhibitors as monotherapy in patients with recurrent or metastatic OSCC who have failed conventional treatments. Clinical trials have proven to yield sustained responses and enhance survival rates in some patients, particularly those with high PD-L1 expression levels. These results provide evidence of the potential of PD-L1-I as a useful tool in the treatment of OSCC patients with the least number of therapeutic options [37].

Besides that, the combined therapies that have PDL-1 inhibitors in common with other drugs, for example, chemo or targeted therapies, are also being considered. These combination approaches aim to enhance the immune response while simultaneously targeting other pathways involved in OSCC progression. Few studies suggest that combination therapies may offer improved response rates and survival outcomes compared to monotherapy alone [18, 19].

Moreover, present research efforts are focused on locating prognostic biomarkers for more precise identification of patients who will benefit from anti-PD-L1 therapy. Mainly, a high PD-L1 expression has been linked to good treatment responses; however, not every patient with high PD-L1 levels is therapy responsive. Hence, there is a pool of biomarkers other than PD-L1, such as tumor mutational burden (TMB) or immune cell infiltration, which are now thoroughly researched for elaborate patient selection and better treatment outcomes [38].

Emerging evidence continues to reinforce the central role of PD-L1 in modulating anti-tumor immune responses and shaping therapeutic outcomes. Recent studies demonstrate that enhancing PD-L1-targeted strategies—whether through adjunctive approaches like phototheranostics or by accounting for tumor-resident microbiota—can significantly improve immune activation and treatment efficacy. These findings underscore the therapeutic potential of refining PD-L1 modulation in the tumor microenvironment and highlight the importance of integrating such innovations into future clinical frameworks [39–41].

In conclusion, PD-L1 expression in OSCC is modulated by a range of biological, hormonal, and environmental factors—including sex, HPV status, lifestyle behaviors, and tumor differentiation—highlighting its complex role in tumor immune evasion. Tumors with poor differentiation and advanced stage often exhibit higher PD-L1 expression, suggesting its potential as a marker of tumor aggressiveness. However, while being linked to a few clinicopathological features, PD-L1 has not been a sole predictor of OS, DFS, and response to immunotherapy. Variability of results across studies echoes the challenges in relying solely on PD-L1 expression to be a consistent prognostic or predictive biomarker in OSCC. Procedurally, PD-L1 inhibitors have started marking the road as one of the most remarkable means of therapy with recurrent or metastatic OSCC patients as a special beneficiary group, unresponsive to conventional treatments. The outcome of monotherapy with PD-L1 inhibitors has been long-lasting in some cases, especially in those with elevated PD-L1 expression. Additionally, combination therapies that integrate PD-L1 blockade with chemotherapy or targeted agents are showing potential to improve outcomes by targeting multiple oncogenic and immunosuppressive pathways.

Ongoing research is increasingly focused on identifying more precise biomarkers—such as TMB or immune cell infiltration—to better predict which patients will benefit from PD-L1-targeted therapies. These efforts aim to refine patient selection and improve therapeutic outcomes.

In summary, while PD-L1 remains a key player in OSCC immune evasion and a valuable therapeutic target, its prognostic significance remains limited. Future studies should prioritize standardized methodologies, robust biomarker development, and deeper exploration of PD-L1 biology to optimize its clinical utility in OSCC management.