Immune, Vascular, and Metabolic Pathways Linking SARS-CoV-2 to Oncogenesis and Long-Term Disease

Immune, Vascular, and Metabolic Pathways Linking SARS-CoV-2 to Oncogenesis and Long-Term Disease

Esra Hassan, PhD, MSc, GMBPsS

The SARS-CoV-2 pandemic has reshaped our understanding of infectious diseases, not only through acute respiratory illness but also via long-term biological effects. COVID-19 may leave lasting imprints on the immune system, metabolic regulation, and vascular health systems closely linked to cancer biology. Unlike classic oncogenic viruses such as HPV or hepatitis B and C, SARS-CoV-2 is not conventionally classified as cancer-causing. However, it can induce immune dysregulation, chronic inflammation, and organ-specific injury, all biologically plausible contributors to cancer initiation or progression over years or decades (Jaiswal et al., 2024; Ochilov et al., 2025). This piece aims to simply explore some of the emerging evidence on the potential long-term oncogenic effects of SARS-CoV-2.

SARS-CoV-2 Infection: A Multi-System Perturbation

SARS-CoV-2 triggers a cascade of immune, vascular, metabolic, and neurological disturbances that vary in persistence across age groups. In adults, post-COVID sequelae include sustained lymphopenia, NK-cell dysfunction, endothelial injury, and neuroinflammatory changes, while children and adolescents exhibit prolonged vascular and inflammatory abnormalities alongside emerging metabolic disturbances (Sampri et al., 2025; Zeng et al., 2025). Collectively, these systemic effects intersect with key pathways involved in oncogenesis, including impaired tumour immune surveillance, chronic inflammation, endothelial dysfunction, metabolic dysregulation, and epigenetic alterations.

NHS England data indicate a rise in immune dysfunction-related disorders, including autoimmune and inflammatory syndromes, since 2020. This suggests that SARS-CoV-2 may exert a persistent influence on host immunity, potentially contributing to cancer after a 10–20 year latency period.

Adult Immune Dysregulation and SARS-CoV-2

SARS-CoV-2 infection induces perturbations in the adult immune system, which can persist long after the acute phase. Longitudinal cohort studies report sustained lymphopenia, NK-cell exhaustion, and impaired T-cell responses persisting six to twelve months post-infection (NIH, 2023; Zeng et al., 2025). Immune surveillance coordinated activity of T-cells, B-cells, and NK-cells are particularly crucial for recognising and eliminating emerging malignant cells. SARS-CoV-2 disrupts these functions which reduce the capacity for tumour surveillance and may theoretically facilitate cancer recurrence or progression consequently.

Emerging data suggest that SARS-CoV-2 itself damages or reshapes immune memory.  Infection patterns have not returned to pre-pandemic norms. Bacterial diseases such as Mycoplasma pneumoniae, invasive group A streptococcus, and rare infections in infants born long after lockdowns have surged, disproportionately affecting those recovering from COVID-19 compared with influenza or RSV. Immunologists hypothesize that SARS-CoV-2 may impair immune memory or induce a form of immune “reset,” characterised by unusually high, indiscriminate T-cell killing reminiscent of measles-induced immune amnesia. This hypothesis is supported by widespread reactivation of latent viruses, particularly Epstein-Barr virus (EBV) and varicella-zoster, with COVID-19 patients exhibiting more than double the rate of EBV reactivation and a 15% increased risk of shingles in adults over 50 (Tsergas, 2025). These findings suggest SARS-CoV-2 may leave long-lasting scars on the immune system, increasing susceptibility to a broad range of pathogens. These immune perturbations could theoretically compromise tumour surveillance and promote oncogenesis.

Mechanistically, Jahankhani & Ahangari (2023) synthesised over 120 studies to provide one of the most detailed mechanistic assessments to date, drawing on molecular, immunological, and clinical studies. Their review highlights that COVID-19 produces hallmark biological conditions associated with cancer, beginning with immune suppression. The findings highlighted that COVID-19 induces:

·       30–70% reductions in CD4⁺ and CD8⁺ T-cells (Gao et al., 2023)

·       Up to 55% decreases in NK-cell cytotoxicity

·       2–5-fold increases in exhaustion markers (PD-1, TIM-3).

These impair tumour surveillance. SARS-CoV-2 infection also induces sustained activation of pro-inflammatory cytokines:

·       IL-6 rises 10–100×

·       TNF-α 4–10×

·       IL-1β is significantly elevated

These changes activate oncogenic signalling pathways, including NF-κB, STAT3, and JAK, promoting proliferation, angiogenesis, and immune evasion. Viral proteins downregulate RB1 and activate E2F transcription factors, promoting G1–S phase transition and genomic instability. Elevated reactive oxygen species (3–6×) and impaired DNA-damage responses, including dysregulation of ATM/ATR pathways (pathways essential for genome protection), further create a DNA-damaging environment. Additional mechanisms noted in the review included mitochondrial dysfunction, metabolic reprogramming (e.g., altered glycolysis and disrupted fatty-acid metabolism) which resemble cancer-associated metabolic states (Jahankhani & Ahangari, 2023).

Clinical observations align with these mechanistic findings. Clinically, there is a documented increase in cancer recurrence and more aggressive disease trajectories in immune-compromised patients following COVID-19 (Klein, 2023). In support, PolyBio-supported studies of 100–250 recovered patients identified persistent immune dysregulation and metabolic disturbances, including altered cytokine profiles and reduced absolute lymphocyte counts (PolyBio, 2025; Lage et al., 2025 preprint). Collectively, these findings may indicate that SARS-CoV-2 may compromise immune surveillance. However, causality between SARS-CoV-2 and new cancers is unproven presently. These immune perturbations merely highlight plausible mechanisms for oncogenesis.

Hematologic Malignancies

Emerging evidence suggests hematologic cancers may be particularly sensitive to post-COVID immune disruption. Observational reports describe cases in which cancers previously in remission, including lymphoid malignancies, have recurred following SARS-CoV-2 infection (De Winter et al., 2021; Patel, 2024).

A retrospective cohort study of 2,348 patients with prior hematologic cancers found that those who contracted SARS-CoV-2 had higher rates of disease recurrence and progression compared with uninfected controls. Follow-up ranged from 6 to 18 months post-infection, and adjusted analyses demonstrated that prior COVID-19 infection was associated with a 1.6-fold increased risk of hematologic cancer progression (HR 1.63, 95% CI 1.21–2.19), likely due to impaired lymphocyte-mediated tumour surveillance (Klein, 2023).

Cytokine profiling in patients with hematologic cancers revealed elevated TNF-α, IFN-β, TSLP, and soluble VCAM-1 post-COVID infection. These molecules drive proliferation, immune evasion, angiogenesis, and metastasis, with some cytokines remaining persistently elevated for months (De Winter et al., 2021). Cytokine-mediated inflammation can induce DNA damage, epigenetic alterations, and activate pro-tumour signalling pathways (CHOP, 2025).

Mouse models also suggest that viral-induced inflammation can reactivate dormant disseminated cancer cells through IL-6-mediated mechanisms, emphasising the role of chronic post-infectious inflammation in oncogenesis (Chia et al., 2025). The study demonstrated that influenza and SARS-CoV-2 infections “awaken” dormant disseminated breast cancer cells in the lungs of mouse models.

Molecular Mechanisms

SARS-CoV-2 can disrupt tumour suppressor mechanisms. TP53 expression is significantly reduced in severe COVID-19, with suppression persisting for at least 24 weeks. Viral proteins Nsp2 and Nsp3 interfere with p53 via mitochondrial pathways or promote its degradation through RCHY1 ubiquitin ligase. Pathways associated with apoptosis and DNA repair are similarly dysregulated (Gómez-Carballa et al., 2022).

A broader mechanistic review by Ogarek et al. (2023) synthesised evidence from over 150 studies to explore how SARS-CoV-2 could influence cancer risk through multiple biological pathways. Molecular mechanisms included:

·       CD4⁺/CD8⁺ lymphopenia and NK-cell cytotoxicity reduction

·       Persistent cytokine elevation: IL-6 (10–100×), TNF-α and IL-1β (several-fold)

·       Oncogenic JAK/STAT3 and NF-κB activation

·       Suppression of tumour suppressors p53 and Rb, disruption of ATM/ATR DNA-repair signalling

·       Oxidative stress (3–5× ROS elevation) and mitochondrial dysfunction

·       Epigenetic remodelling and metabolic reprogramming (Ogarek et al., 2023).

Organ-Specific Cancer Risks

Pancreatic and Gastrointestinal Cancers

Prior infections with SARS-family viruses are associated with an increased long-term risk of pancreatic adenocarcinoma, with hazard ratios ranging from 1.38 to 1.52 over 10–20 years, as observed in a cohort of 4,782 patients (Jaiswal et al., 2024; Sadrabadi et al., 2021). The proposed mechanisms include chronic inflammation, persistent immune dysregulation, sustained cytokine activity, endothelial injury, and metabolic perturbations. Given that SARS-CoV-2 shares immunopathological features with SARS-CoV, it may similarly predispose individuals to pancreatic malignancies through these same pathways, highlighting a potential long-term cancer risk following COVID-19 infection.

Lung Cancer

A recent preprint by Qian et al. (2025) provides mechanistic evidence that severe respiratory viral infections, including SARS-CoV-2 and influenza, can accelerate lung cancer development by reshaping the lung’s immune and epithelial landscape. Retrospective clinical analysis showed higher subsequent lung cancer incidence in patients hospitalised with COVID-19, while mouse models revealed accelerated tumour growth, reduced survival, and profound lung microenvironment changes following prior viral infection. Mechanistically, viral pneumonia induced long-lived epigenetic changes, creating a pro-tumour niche characterised by SiglecF^hi tumour-associated neutrophils and persistent injury-associated epithelial cell states locked in tumour-prone differentiation. Sustained chromatin remodelling at cytokine loci established an “inflammatory memory” that suppresses anti-tumour immunity.

Breast and Hormone-Sensitive Cancers

Emerging evidence suggests that SARS-CoV-2 may influence hormone-sensitive cancers by reshaping inflammatory and hormonal signalling pathways. Preclinical work shows that virus-induced cytokines can alter oestrogen receptor expression and stromal–epithelial interactions, with data from 512 breast tissue biopsies linking post-infection cytokine elevation to increased cellular proliferation and DNA damage (Shen et al., 2025). Similar modulation of hormone receptors has been observed in breast and prostate models (2025).

Viral-Associated Cancers

Broader oncogenic implications are supported by a large international cohort study of 1,281,997 infected and matched uninfected women, where prior SARS-CoV-2 infection was associated with significantly increased risks of HPV-related cancers over three years (67% higher for cervical cancer, 131% for vaginal, 98% for vulvar, 92% for anal, and 78% for oropharyngeal cancer), alongside elevated risks for multiple carcinoma-in-situ outcomes (e.g., HR 1.336 for cervical CIS and up to 1.960 for anal CIS) (Shih et al., 2025). These findings suggest that COVID-19–induced immune and inflammatory dysregulation may accelerate tumorigenesis in viral-associated cancers.

COVID-19 Long-Term Organ/System Effects – Oncogenic Risk

Organ / System	Oncogenic Risk / Mechanism
Immune System	Chronic immune dysregulation → impaired tumour surveillance (Persistent T/NK dysfunction and cell exhaustion, chronic inflammation)
Endothelium / Vascular System (Adults & children)	Microvascular injury, thrombosis, oxidative stress → DNA damage, pro-tumour microenvironment (endothelial activation + persistent inflammatory markers)
Hematologic / Lymphoid Malignancies	↑ recurrence/progression post-COVID; accelerated relapse pathways
Neurological / Alzheimer’s-linked pathways	Neuroinflammation, oxidative stress → potential neuro-oncogenic processes (Microglial activation & tau pathology; dementia risk post-COVID)
Pancreatic / GI cancers	Inflammation-driven oncogenesis; metabolic dysregulation
Breast / Hormone-sensitive cancers	Hormone signalling disruption + chronic inflammation → tumorigenesis (↑ Ki-67, DNA damage)
Metabolic / Endocrine (diabetes, insulin resistance)	Dysregulated insulin/IGF pathways → tumour growth; metabolic reprogramming
Direct viral oncogenic mechanisms (p53, Rb, ATM/ATR disruption)	Genomic instability → potential oncogenesis
General inflammatory priming (long-term IL-6, TNF-α, IFN dysregulation)	Chronic inflammation → multi-tissue malignant transformation (persistent immune signalling dysregulation)
Paediatric long-term immune & vascular injury	Early-life immune/vascular perturbation → lifetime cancer susceptibility (thrombosis and myocarditis post-Covid)

Case Reports

Rare cases, such as disseminated Kaposi sarcoma (KS) in an immunocompetent adult post-COVID, suggest transient immune dysregulation may reactivate latent oncogenic viruses (Gardini et al., 2021). Moreover, a study by Pietroluongo et al. (2024) reports a case series of patients with Kaposi’s sarcoma whose tumours progressed following SARS‑CoV‑2 infection and complements this with a systematic review of the literature. The authors searched PubMed and EMBASE for studies using terms related to KS, HHV‑8, and COVID‑19, including case reports and mechanistic studies. They found that acute SARS‑CoV‑2 infection may trigger immune dysregulation, lymphopenia, and elevated pro-inflammatory cytokines (notably IL‑6), potentially reactivating latent HHV‑8 and promoting KS progression. While no large-scale epidemiological statistics were reported, the temporal association across cases suggests a possible interplay between COVID-19 and KS, highlighting the need for clinical vigilance and further research into virus-driven cancer progression.

Vascular, Metabolic, and Neurological Sequelae Relevant to Cancer

Beyond immune dysregulation, COVID-19 has been associated with elevated risks of vascular, metabolic, and neurological disorders in adults. Chronic inflammation and endothelial activation were observed in both preclinical and population-level studies of COVID-19 patients (Jiaswal et al., 2024; Shen et al., 2025). Persistent inflammation promotes DNA damage and epigenetic changes, endothelial injury creates hypoxic, tumour-prone microenvironments, and metabolic derangements such as insulin resistance and type 2 diabetes, activate pro-oncogenic signalling via IGF-1 and mTOR pathways (Kwan et al., 2023; Lage et al., 2025, preprint; PolyBio, 2025).

Neurologically, long-COVID patients show microglial activation, tau phosphorylation, and Alzheimer-like pathology (Jiang et al., 2024). Adults over 50 exhibit 58% higher risk of all-cause dementia and 105% higher risk of vascular dementia post-infection (Shan et al., 2025). These findings suggest that systemic inflammation extend beyond respiratory outcomes. Chronic neuroinflammation can promote oxidative stress, impair DNA repair, and indirectly contribute to oncogenesis (Shan et al., 2025).

Paediatric Considerations

Children and adolescents are not immune to post-infectious complications.

Vascular risk

In one retrospective, population-based cohort study of nearly 14 million people under 18 year-olds in England, 28.1% with COVID-19 exhibited elevated risks for rare vascular and inflammatory events and reported post-COVID complications. Specifically, within the first week post-diagnosis, hazard ratios were significantly increased for arterial thromboembolism (aHR 2.33, 95% CI 1.20–4.51), myocarditis or pericarditis (aHR 3.46, 2.06–5.80), and inflammatory conditions (aHR 14.84, 11.01–19.99). Persistent risks remained up to 12 months post-infection (Sampri et al., 2025). Vaccination risk of myocarditis was substantially lower than Covid infection-related myocarditis (Sampri et al., 2025).

Microvascular dysfunction and alterations were also observed in a study involving paediatric patients at The Children’s Hospital of Philadelphia (CHOP, 2025). 200 children several months post-COVID infection had elevated biomarkers associated with blood vessel injury, including VCAM-1 and ICAM-1. Microvascular injury and tissue hypoxia are known contributors to a pro-tumorigenic microenvironment.

Diabetes risk

The endocrine consequences of COVID-19 are increasingly evident, particularly regarding the development of diabetes. Miller et al. (2024) reported that in a cohort of 34,000 paediatric patients, SARS-CoV-2 infection was associated with a 1.5–2-fold increased risk of new-onset type 2 diabetes compared with uninfected controls (Miller et al., 2024). Independent reports support these findings, highlighting systemic metabolic dysregulation following COVID-19, including altered insulin signalling, insulin resistance, chronic inflammation, and mitochondrial dysfunction (Kwan et al., 2023; PolyBio, 2025). These metabolic disturbances may indirectly elevate long-term cancer risk, particularly in endocrine-sensitive tissues (Lage et al., 2025, preprint).

Implications and Conclusions

Collectively, the evidence indicates that SARS-CoV-2 infection triggers a cascade of immune, vascular, metabolic, and neurological perturbations that converges on pathways known to facilitate cancer. Adults show sustained immune dysregulation, endothelial injury, and neuroinflammation, whereas children exhibit prolonged vascular, inflammatory, and metabolic risks.

While direct causal links between COVID-19 and cancer remain under investigation over time, mechanistic, epidemiological, and clinical evidence supports biologically plausible pathways.

References

Chia, S.B., Johnson, B.J., Hu, J. et al. Respiratory viral infections awaken metastatic breast cancer cells in lungs. Nature 645, 496–506 (2025).

CHOP. (2025). Researchers find elevated biomarker related to blood vessel damage in children after SARS-CoV-2. Children’s Hospital of Philadelphia. https://www.chop.edu/news/chop-researchers-find-elevated-biomarker-related-blood-vessel-damage-all-children-sars-cov-2

De Winter, F. H., Hotterbeekx, A., Huizing, M. T., Konnova, A., Fransen, E., Jongers, B. S., ... & Kumar-Singh, S. (2021). Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients. Cancers, 13(22), 5718.

https://www.medscape.com/viewarticle/965499?form=fpf

Dresden.B.P., & Alcorn, J.F. (2025). Inflammation during viral infection can rouse dormant cancer cells. https://www.nature.com/articles/d41586-025-02137-1

Gao, F., Mallajosyula, V., Arunachalam, P. S., van der Ploeg, K., Manohar, M., Röltgen, K., ... & Davis, M. M. (2023). Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection. Immunity, 56(4), 864-878.

Gardini, G., Odolini, S., Moioli, G. et al. Disseminated Kaposi sarcoma following COVID-19 in a 61-year-old Albanian immunocompetent man: a case report and review of the literature. Eur J Med Res 26, 152 (2021).

Jahankhani, K., Ahangari, F., Adcock, I. M., & Mortaz, E. (2023). Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent?. Biochimie, 213, 130-138.

Jaiswal, A., Shrivastav, S., Kushwaha, H.R. et al. Oncogenic potential of SARS-CoV-2—targeting hallmarks of cancer pathways. Cell Commun Signal 22, 447 (2024).

Jiang, Y., Neal, J., Sompol, P., Yener, G., Arakaki, X., Norris, C. M., ... & Hajós, M. (2024). Parallel electrophysiological abnormalities due to COVID‐19 infection and to Alzheimer's disease and related dementia. Alzheimer's & Dementia, 20(10), 7296-7319.

Klein, H.E. (2023). Kashyap Patel, MD, Sees Link Between COVID-19 and Cancer Progression, Calls for More Biomarker Testing.

Kwan, A. C., Ebinger, J. E., Botting, P., Navarrette, J., Claggett, B., & Cheng, S. (2023). Association of COVID-19 vaccination with risk for incident diabetes after COVID-19 infection. JAMA Network Open, 6(2), e2255965-e2255965.

Lage et al. (2025). Preprint. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. https://www.medrxiv.org/content/10.1101/2025.04.16.25325949v1

Miller, M. G., Terebuh, P., Kaelber, D. C., Xu, R., & Davis, P. B. (2024). SARS-CoV-2 infection and new-onset type 2 diabetes among pediatric patients, 2020 to 2022. JAMA Network Open, 7(10), e2439444-e2439444.

NIH. (2023). SARS-CoV-2 infection weakens immune-cell response to vaccination. https://www.nih.gov/news-events/news-releases/sars-cov-2-infection-weakens-immune-cell-response-vaccination

https://uknow.uky.edu/research/uk-researchers-find-alzheimer-s-brain-changes-long-covid-patients

Ochilov, et al. (2025). Silent invasion: COVID-19’s hidden damage to human organs. Preprints.org. https://www.preprints.org/manuscript/202507.0013/v1

Pietroluongo, E., Luciano, A., Peddio, A., Buonaiuto, R., Caltavituro, A., Servetto, A., ... & Giuliano, M. (2024). Exploring the interplay between Kaposi's sarcoma and SARS‐CoV‐2 infection: A case series and systematic review. Journal of Medical Virology, 96(8), e29849.

PolyBio. (2025). Polybio-supported study reveals long-term immune and metabolic damage after COVID-19 infection. https://polybio.org/polybio-supported-study-reveals-long-term-immune-and-metabolic-damage-after-covid-19-infection/

Qian, W. et al., (2025). Preprint. Respiratory viral infections prime accelerated lung cancer growth. https://www.biorxiv.org/content/10.1101/2025.09.02.672566v1

Sadrabadi, E.A., Bereimipour, A., Jalili, A. et al. The risk of pancreatic adenocarcinoma following SARS-CoV family infection. Sci Rep 11, 12948 (2021).

Sampri, A., Shi, W., Bolton, T., Ip, S., Knight, R., Walker, V., Denholm, R., Raffetti, E., Keene, S., Allara, E., Jiang, X., Kontopantelis, E., Denaxas, S., Khunti, K., Conrad, N., Pagel, C., Hardelid, P., Sterne, J. A. C., Brown, K. L., … Wood, A. M. (2025). Vascular and inflammatory diseases after COVID-19 infection and vaccination in children and young people in England: A retrospective, population-based cohort study using linked electronic health records. The Lancet Child & Adolescent Health, 9(12), 803–818.

Shan, D., Xu, Y., Yang, C. et al. COVID-19 infection associated with increased risk of new-onset vascular dementia in adults ≥50 years. npj Dement. 1, 28 (2025).

Shen, W., Guo, Y., Ai, C., Wang, X., & Li, G. (2025). The double-edged sword: How SARS-CoV-2 might fuel lung cancer: Investigating the potential oncogenic mechanisms of the novel coronavirus in lung carcinogenesis. Molecular Aspects of Medicine, 106, 101413.

Shih, Y. H., Yang, C. Y., & Lung, C. C. (2025). SARS-CoV-2 infection heightens the risk of developing HPV-related carcinoma in situ and cancer. Discover Oncology, 16(1), 1552.

Tsergas, N. (2025). Why scientists are rethinking the immune effects of SARS-CoV-2. bmj, 390.

Zeng, L., Liu, L., Ren, B., Feng, B., Lai, X., Lai, X., ... & Hong, W. (2025). Distinct characteristics of T cell receptor repertoire associated with the SARS-CoV-2 reinfection. Frontiers in Immunology, 16. 

*ChatGPT was used to organise the research papers into themes for this piece and to create the structure of the blog.