Malignancy Risk in Long COVID

Dr Graham Exelby May 2025

Overview:

Emerging data suggest a potential increase in malignancy risk following SARS-CoV-2 infection. 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.

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.

2. RAGE and TLR4 Looping Activation:

• RAGE and TLR4 are activated by viral debris, DAMPs, and advanced glycation end-products.

• Their signalling pathways converge on NF-κB and STAT3, both implicated in tumour initiation, immune escape, and angiogenesis.

• Chronic activation of these receptors is associated with colorectal, renal, hepatic, and breast malignancies.

3. Immune Exhaustion and Impaired Immunosurveillance:

•  Long COVID is associated with lymphopenia, T cell exhaustion (PD-1, TIM-3 expression), and altered NK cell profiles.

• Reduced cytotoxic clearance of neoplastic cells and latent oncogenic viruses (e.g., EBV) may enable malignant transformation.

4. Epigenetic Reprogramming and DNA Damage:

•  Persistent oxidative stress and NAD⁺ depletion reduce DNA repair capacity.

• PARP overactivation and mitochondrial dysfunction lead to increased mutation burden.

• Epigenetic silencing of tumour suppressor pathways may occur under chronic inflammation.

5. Spike Protein and Oncogenic Signalling Crosstalk:

• 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.

Clinical Implications:

• Increased vigilance is warranted in patients with persistent inflammatory markers, lymphopenia, or post-viral reactivation syndromes.

• Malignancy screening should be considered in those with new-onset symptoms (weight loss, pain, masses, anemia) without obvious cause.

• Autoimmunity, prolonged immunosuppression, or overlapping paraneoplastic syndromes should heighten suspicion.

Summary:

The malignancy risk in Long COVID may be driven by a convergence of chronic inflammation, impaired immune clearance, and DNA instability. While not definitively proven, mechanistic parallels with tumour microenvironment biology support the need for cautious clinical monitoring and research into long-term oncogenic outcomes.