Severe COVID-19 or flu infection linked to higher lung cancer risk years later

New research published this week found that severe cases of COVID-19 or influenza can trigger lasting changes in lung immune cells that may significantly raise the risk of developing lung cancer in the years that follow. The study identified specific immunological alterations in lung tissue that persist long after the acute infection has resolved, creating conditions that support tumor development. For the millions of people who were hospitalized with severe COVID-19 between 2020 and 2023, this finding has direct implications for how their long-term health should be monitored.

This is not the first study to link chronic inflammation to cancer risk. That connection has been established in other organs, most clearly in the gastrointestinal tract, where long-term inflammation from Helicobacter pylori infection raises the risk of stomach cancer, and where inflammatory bowel disease elevates colorectal cancer risk. What makes this research notable is that it identifies a specific molecular pathway through which a respiratory virus triggers the kind of immune cell reprogramming that creates a pro-cancerous environment in the lung.

What happens in the lung after severe infection

In healthy lungs, the immune response to infection is self-limiting. Immune cells arrive, fight the pathogen, and then either clear or settle into a surveillance state. In severe respiratory infections, that process goes wrong. The inflammatory response is prolonged and intense, and some immune cells, particularly macrophages and T cells, undergo what researchers call exhaustion, a state where they lose their normal regulatory function and instead produce a sustained stream of pro-inflammatory cytokines.

The study found that this exhausted immune cell state persists in lung tissue for at least 12 months after severe COVID-19 or influenza, based on analysis of lung samples from patients who had recovered from severe infection and comparison with samples from individuals who had experienced only mild or no respiratory illness. The exhausted immune cells produced elevated levels of interleukin-6 and tumor necrosis factor-alpha, two cytokines that are already associated with cancer progression in existing literature. Sustained high levels of those cytokines suppress the activity of natural killer cells, which are the immune system's primary defense against early-stage tumor cells.

The natural killer cell suppression mechanism

Natural killer cells patrol tissues looking for cells that display markers of stress, DNA damage, or abnormal growth. When they find such cells, they destroy them before a tumor can establish itself. This surveillance function is one of the body's primary defenses against early malignancy, and it works continuously in healthy tissue. The research showed that in lungs with persistent post-infection inflammation, natural killer cell activity was suppressed by approximately 40 percent compared to matched controls, measured by a standard cytotoxicity assay.

A 40 percent reduction in natural killer cell activity is not a small number. It means the lung's early-detection immune system is operating at significantly reduced capacity for an extended period following severe infection. During that window, any cells that develop early mutations have a higher chance of surviving and replicating without immune clearance. The researchers modeled that this window of reduced surveillance, if it persists for 12 to 18 months post-infection, could meaningfully increase the cumulative probability of a malignant cell escaping detection, particularly in individuals who already have other lung cancer risk factors such as smoking history or occupational exposure to carcinogens.

Why this matters more for COVID-19 survivors specifically

Influenza has caused severe lung disease for over a century, and its long-term pulmonary consequences have been studied for decades. COVID-19 is different in two ways that are relevant here. First, SARS-CoV-2 directly infects type II pneumocytes, the cells lining the deep lung that are responsible for gas exchange and surfactant production, causing direct cellular damage at a site where early lung adenocarcinomas frequently originate. Seasonal influenza viruses primarily target the upper respiratory tract and larger airways rather than the deep lung tissue.

Second, the scale of severe COVID-19 exposure was unprecedented. The World Health Organization estimated that more than 7 million people were hospitalized with severe COVID-19 globally between 2020 and 2022 alone. If the immune cell changes identified in this study translate to even a modest increase in lung cancer incidence in that population, the absolute number of additional cancer cases over the next decade would be substantial. Lung cancer already causes more deaths globally each year than breast, colorectal, and prostate cancers combined, according to the Global Cancer Observatory's 2024 data.

What the researchers say should change in clinical practice

The study's authors recommended that patients who were hospitalized with severe COVID-19 or severe influenza should be considered for enhanced long-term pulmonary monitoring, including low-dose CT screening at intervals closer than those currently recommended for standard high-risk populations. Current US Preventive Services Task Force guidelines recommend annual low-dose CT screening for adults aged 50 to 80 with a 20 pack-year smoking history who currently smoke or quit within the past 15 years. The researchers argue that severe respiratory viral infection should be added as an independent risk factor that qualifies patients for similar surveillance, regardless of smoking history.

The study was conducted by researchers at the University of California San Francisco and the Gladstone Institutes, and was published in the journal Nature Immunology. The team is currently enrolling participants in a five-year prospective cohort study that will track lung cancer incidence in severe COVID-19 survivors compared to matched controls who experienced only mild illness. Enrollment for that study is open through June 2026 at UCSF Medical Center and three affiliated sites.