Malignancy Risk in Long COVID

Overview for GPs

Dr Graham Exelby June 2025

Overview:

Emerging data and clinical experience suggest a potential increase in malignancy risk following SARS-CoV-2 infection. While published epidemiological evidence remains limited, clinicians working in Long COVID and immunology are increasingly recognizing early warning signals, particularly in high-risk subgroups.

This may be particularly relevant in Long COVID patients, where chronic inflammation, immune exhaustion, and impaired DNA repair persist. While causality remains under investigation, plausible mechanisms point to an altered cellular microenvironment that favours oncogenesis. Early monitoring and mechanistically-informed clinical vigilance are warranted.

The mechanisms described are supported by preclinical studies and early clinical observations, but large-scale human studies are ongoing.

Mechanisms Contributing to Oncogenic Risk in Long COVID:

1.     Chronic Inflammation and NF-κB Activation:

Sustained low-grade inflammation leads to continuous NF-κB signalling, promoting anti-apoptotic, pro-proliferative gene expression.   Inflammatory cytokines such as IL-6, TNF-α, and CCL2 contribute to tissue microenvironmental changes, similar to tumour-promoting niches.

This leaves oncogenic viruses (EBV, HPV) unchecked and reduces immunosurveillance against early neoplasms.

2.     RAGE–TLR4–STAT3 Axis:

The RAGE–STAT3–CCL2 axis functions not only as an inflammatory amplifier but also as a well-established oncogenic program.   RAGE and TLR4 are activated by viral debris, DAMPs, and advanced glycation end-products.   RAGE is strongly upregulated under hypoxia which further facilitates epithelial-to-mesenchymal transition (EMT), especially in mucosal and vascular tissues, a hallmark of invasive cancer.

These RAGE and TLR receptors activate NF-κB and STAT3, upregulating IL-6, VEGF, Bcl-2, and CCL2. These mediators facilitate tumour angiogenesis, immune evasion, and survival.

CCL2 promotes recruitment of tumour-associated macrophages (TAMs), which foster angiogenesis, immune evasion, and stromal remodeling.   Meanwhile, STAT3 upregulates VEGF, Bcl-2, and survivin, enhancing malignant cell persistence.  

3.     Immune Exhaustion and Natural Killer (NK) Cell Suppression:

 In Long COVID, NK cells exhibit both quantitative and qualitative suppression—reduced in number and exhibiting decreased perforin, granzyme B, and CD16 expression. This is compounded by persistent IL-6 and STAT3 signalling, which downregulate cytotoxicity while upregulating survival signals in transformed cells.

Natural killer (NK) cells, vital for early tumour cell clearance, show functional suppression and senescence in Long COVID, with reduced perforin and granzyme B activity. 

Chronic IL-6 and STAT3 signalling further impairs cytotoxic responses and promotes immune tolerance toward emerging neoplastic cells.   This compromises tumour immunosurveillance, particularly in individuals with latent oncogenic viruses (e.g., EBV, HPV).

4.     Epigenetic Reprogramming and DNA Damage:

Oxidative stress, NAD⁺ depletion, and PARP overactivation reduce DNA repair fidelity.Chronic inflammation can lead to epigenetic silencing of tumour suppressor genes and increased mutational burden.

5.     Spike Protein and Oncogenic Signalling Crosstalk:

The spike protein may also indirectly enhance oncogenic signaling via TLR2/4–RAGE interactions, compounding the NF-κB–STAT3 inflammatory loop.   Spike protein interaction with integrins and toll-like receptors may alter MAPK, ERK, and PI3K-AKT signalling.  These pathways are involved in cellular growth, migration, and transformation when dysregulated.

6.     Mast Cells and Microenvironmental Priming:

Mast cells activated by RAGE and TLR4 release histamine, tryptase, and matrix metalloproteinases, promoting vascular permeability and ECM degradation.  This primes the tissue microenvironment for stromal remodelling, angiogenesis, and tumour invasion, particularly in lung, breast, and GI tract.

Clinical Implications:

• Increased clinical vigilance is warranted in patients with persistent inflammatory markers, lymphopenia, or signs of immune dysregulation.

• Consider malignancy screening in patients with unexplained weight loss, fatigue, pain, anemia, or reactivation syndromes.

• Patients with coexisting autoimmune disease, prolonged immunosuppression, or paraneoplastic features may require escalation of care.

Summary:

The malignancy risk in Long COVID may stem from a persistent inflammatory microenvironment involving dysregulated RAGE–NF-κB–STAT3 signalling, immune exhaustion, mast cell activation, and impaired DNA repair. NK cell suppression and epigenetic instability create an immunologically permissive and metabolically stressed tissue niche.

While direct causal links are still emerging, these mechanisms support a cautious clinical stance, including low-threshold screening in high-risk patients and ongoing research into immune-metabolic drivers of post-viral oncogenesis.