Corona virus disease 2019 (COVID-19), characterized by a range of febrile and respiratory symptoms with potentially lethal risks caused by SARS-CoV-2, has garnered widespread global attention since its initial report. After three years of a global pandemic, COVID-19 has resulted in over 700 million infections, leading to millions of deaths (1–3). While the vast majority of COVID-19 patients have recovered, some individuals still experience Post-COVID-19 symptoms, indicating its long-term effects on various organ functions (4).

Laryngeal cancer primarily manifests as squamous cell carcinoma within the larynx. The global annual incidence rate stands at 2.76 per 100,000 inhabitants, with higher prevalence among men than women. Its causes are linked to smoking, alcohol consumption, exposure to physical and chemical stimuli, and variations in hormone secretion levels (5, 6). As a malignant tumor localized in the larynx, laryngeal cancer obstructs patients’ upper respiratory tracts and esophagus, leading to difficulties in breathing and swallowing. Simultaneously, it affects patients’ voices, resulting in hoarseness and articulation challenges (7). Additionally, viral infections, particularly human papilloma virus (HPV), constitute significant risk factors for laryngeal cancer. Studies suggest an approximate 28% HPV infection rate among patients with laryngeal cancer. HPV, upon infecting the larynx, may induce gene mutations and disruptions in gene expression through various mechanisms, thereby causing cell cycle dysregulation, abnormal proliferation, and ultimately leading to the development of laryngeal cancer (8). Furthermore, several studies indicate that HPV-positive patients exhibit a more favorable prognosis than HPV-negative patients, underscoring the role of viral infections in oropharyngeal cancer development and treatment (9–11).

Given that COVID-19 is a viral infection closely associated with the respiratory system, there is curiosity regarding its potential impact on the occurrence of laryngeal cancer through analogous effects. Several case reports have indicated that COVID-19 can prompt acute laryngitis and epiglottitis, hinting at potential adverse effects on laryngeal function (12–14). Previous studies have also highlighted a notable correlation between COVID-19 and the incidence of diverse cancers (15, 16). This has prompted investigations into the potential correlation between COVID-19 and laryngeal cancer. However, laryngeal cancer is a condition with a multifaceted etiology, and conventional randomized controlled studies are susceptible to confounding variables and reverse causation. These studies are also time-consuming and resource-intensive. Hence, this study opts for Mendelian randomization (MR), leveraging genetic variation as an instrumental variable based on Mendel’s law of inheritance. MR helps circumvent confounding factors and reverse causation, allowing for the investigation of the relationship between COVID-19 and laryngeal cancer (17).

In the present study, MR analyses of COVID-19 and laryngeal cancer were conducted using primarily three methods: MR-Egger, IVW, and WME. COVID-19 patients were categorized into three phenotypes based on severity: non-hospitalized, inpatients, and those with severe respiratory symptoms. Figure 2 illustrates the effect estimates of the MR analyses regarding the association between COVID-19 and laryngeal cancer. We utilized IVW, MR-Egger, simple mode, weighted median, and weighted mode-based estimations to assess the causal associations between genetically predicted COVID-19 severity and laryngeal cancer ( Figure 3 ).

For the non-hospitalized COVID-19 patient group, 7 SNP loci were selected as instrumental variables ( Supplementary Table S2 ). The IVW method’s results indicated an Odds ratio (OR) of 0.24 (95% Confidence intervals (CI), 0.05–1.26) with a P-value of 0.09, suggesting no correlation between non-hospitalized COVID-19 patients and laryngeal cancer ( Figure 2 ; Table 1 ). The Cochran Q test showed no heterogeneity (P=0.13), and the MR-Egger intercept test demonstrated no horizontal pleiotropy (P=0.29) ( Table 1 ).

In the COVID-19 inpatient group, 5 SNP loci were chosen as instrumental variables ( Supplementary Table S2 ). The IVW method revealed an OR of 0.51 (95% CI, 0.28–0.95) with a P-value of 0.03, suggesting an inverse correlation between COVID-19 inpatients and laryngeal cancer ( Figure 2 ; Table 1 ). The Cochran Q test showed no heterogeneity (P=0.29), and the MR-Egger intercept test indicated no horizontal multiplicity (P=0.70) ( Table 1 ).

Within the COVID-19 patients exhibiting severe respiratory symptoms, 7 SNP loci were utilized as instrumental variables ( Supplementary Table S2 ). The IVW method showed an OR of 0.62 (95% CI, 0.43–0.90) with a P-value of 0.01, suggesting a significant inverse correlation between COVID-19 patients with severe respiratory symptoms requiring hospitalization and laryngeal cancer ( Figure 2 ; Table 1 ). The Cochran Q test indicated no heterogeneity (P=0.64), and the MR-Egger intercept test revealed no horizontal multiplicity (P=0.74) ( Table 1 ).

The causal effect of each SNP associated with COVID-19 and laryngeal cancer was shown in Supplementary Figure S1 . Leave-one-out sensitivity analysis was performed for each group of COVID-19. Results indicated that after individually removing each SNP, the remaining SNP analysis results closely mirrored the initial analysis, suggesting robust and unbiased data ( Figure 4 ).

It has been demonstrated that COVID-19, as a viral disease, can cause acute inflammation of the larynx and epiglottis (12–14). This suggests that SARS-CoV-2 might have the potential to infect the larynx or pharynx similarly to HPV (8). Patients co-infected with HPV and afflicted with laryngeal or oropharyngeal cancer have also exhibited favorable responses to immunotherapy and chemotherapy (10, 11). HPV infection has been suggested as a prognostic indicator for laryngeal and oropharyngeal cancer. Moreover, as a global pandemic, COVID-19 has left many patients with various degrees of post-recovery sequelae, highlighting the potential long-term effects of COVID-19 infection on organ function (4). This has prompted our interest in investigating the correlation between the severity of COVID-19 infection and laryngeal cancer, with the aim of utilizing MR to explore whether COVID-19 infection can serve as a predictive factor for the onset and prognosis of laryngeal cancer. Few MR studies have explored the relationship between the severity of COVID-19 infection and the risk of various cancers, including laryngeal and oropharyngeal cancers (15, 16). However, these studies have not extensively investigated the specific association between COVID-19 and laryngeal cancer. Our research aims to fill this gap by comprehensively examining the correlation between COVID-19 and laryngeal cancer, while also analyzing potential pathways that may influence this relationship.

Despite HPV being a significant risk factor for oropharyngeal cancer, studies consistently show better outcomes among HPV-positive patients, highlighting viral infections’ pivotal role in oropharyngeal cancer’s development and treatment (9–11). Interestingly, we found similar effect of COVID-19 on laryngeal cancer. Our study reveals a significant correlation between both COVID-19 hospitalized patients (OR=0.51, 95% CI: 0.28–0.95, P=0.03) and patients with severe respiratory symptoms (OR=0.62, 95% CI: 0.43–0.90, P=0.01) and laryngeal cancer, indicating a possible protective role against laryngeal cancer. Such results raise the question of why a disease widely impacting the respiratory system could act as a protective factor for laryngeal cancer. Thus, we commenced our investigation with SNP loci associated with COVID-19. Specifically, five SNP loci related to COVID-19 hospitalized patients and seven SNP loci linked to COVID-19 patients with severe respiratory symptoms were chosen as instrumental variables, with three overlapping loci: rs13050728, rs2109069, rs35081325. These three SNPs are believed to elucidate the correlation between COVID-19 and laryngeal cancer.

Previous research (28) has highlighted the strong connection between a genetic marker, rs13050728, and severe COVID-19 cases, influencing the expression of a key immune gene called interferon alpha receptor 2 (IFNAR2). This gene’s role in both COVID-19 and cancer is being explored in this study. Specifically, the C allele of rs13050728, identified in this research, demonstrates a robust link with heightened IFNAR2 expression, potentially impacting immune response mechanisms (28).

Type I interferons (IFNs), pivotal in combating infections and tumors, have been extensively studied (29–32). In the context of COVID-19, delays in the body’s IFN response have been observed, leading to more severe symptoms in affected individuals (28, 33–36). Interestingly, individuals with severe COVID-19 cases and certain cancer patients display escalated levels of IFNAR2 (37, 38). Multiple studies have also confirmed that high expression of IFNAR2 has a significant impact on the good prognosis of immunotherapy, and has a positive impact on patient survival rate and survival time (39–41). This study underscores IFNAR2’s vital role in immune responses to infections and tumors in both diseases. We propose that interference with IFN α and IFN β hinders type I interferon response, impacting COVID-19 severity and increasing IFNAR2 expression. Maintaining high expression of IFNAR2 and restoring normal levels of type I interferon can effectively inhibit the proliferation of tumor cells, thereby reducing the risk of laryngeal cancer or improving the treatment effect of laryngeal cancer patients during IFN treatment.

Laryngeal cancer, often linked to viral infection, paradoxically exhibits improved prognoses in viral-infection-positive cases. A study assessing anti-PD-1 treatment in nasopharyngeal carcinoma patients who received the COVID-19 vaccine reported higher objective response and disease control rates than the non-vaccinated subgroup (42). Meanwhile, certain related studies have suggested that COVID-19 vaccine administration could enhance the therapeutic efficacy of PD-1 inhibitors in various cancers (43, 44). These studies also suggest that COVID-19 vaccination leads to an increase in CD4+ T cell levels in patients, potentially aiding in the activation of CD4+ T cells and reshaping the tumor microenvironment (43). HPV-positive laryngeal cancer patients display extended survival periods and enhanced sensitivity to treatments like immunotherapy and chemotherapy (45–48). This suggests viral infections both pose a risk for laryngeal cancer and positively impact its prognosis, aligning with our findings. We hypothesize that viral infections activate the immune system, potentially influencing a better prognosis.

Use of MR in our study, employing a European population and the largest COVID-19 GWAS, ensured robustness and minimized confounding factors (19). We validated our selected SNPs as instrumental variables, observing no significant heterogeneity or horizontal pleiotropy. However, limitations exist: (i) the novelty of the COVID-19 outbreak might not reflect short-term outcomes in laryngeal cancer, and high mortality rates early in the pandemic may introduce bias; (ii) while statistical methods addressed current issues, alternative pathways influenced by instrumental variables in laryngeal cancer cannot be entirely ruled out; (iii) due to the limited availability of publicly accessible GWAS data on COVID-19 patients and laryngeal cancer, it is currently not feasible to assess the impact of gender and age on their correlation. Further investigation into COVID-19-related genes and their impact on patients is crucial.

In summary, our research suggests that the exacerbation of COVID-19 infection may be an important factor in reducing the risk of laryngeal cancer, and the increase in IFNAR2 levels may play a significant role in this. This inference underscores the significant role of the type I interferon response in mitigating the risk of laryngeal cancer, thereby suggesting that interferon-related immunotherapy holds substantial promise for both the prevention and treatment of this condition. Furthermore, such immunotherapy interventions may offer considerable potential for reducing tumor staging preoperatively and prolonging survival postoperatively among patients with laryngeal cancer.

In conclusion, genes associated with COVID-19 development might hinder tumor development, potentially lowering laryngeal cancer risk or improving prognoses in severe COVID-19 cases post-immunotherapy. Detailed mechanisms warrant exploration through additional studies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author/s.

Due to the utilization of published studies and publicly available databases, no additional ethical approval from an institutional review board was necessary.

HW: Data curation, Formal analysis, Methodology, Validation, Writing – original draft, Writing – review & editing. NF: Data curation, Methodology, Supervision, Validation, Writing – review & editing. PM: Writing – original draft, Writing – review & editing. RJ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. XW: Funding acquisition, Supervision, Writing – original draft, Writing – review & editing.