New study suggests that COVID-19 may slightly increase the risk of lung cancer by triggering a biological chain reaction in the lungs, driven by the virus’s spike protein, that promotes inflammation, scarring, and tumor-friendly conditions, especially in higher-risk groups like smokers; while the individual risk remains small, the findings are important because they reveal a plausible mechanism and potential targets for prevention and treatment.
In the years since the COVID-19 pandemic began, scientists have worked to understand its long-term consequences. Now, a new international study reveals a concerning possibility: the virus’s spike protein may actively contribute to the development of lung cancer.
Prof. Alex Gileles-Hillel of the Hebrew University of Jerusalem and Hadassah Medical Center, together with Cayleigh Wallace, Dr. Hong Yue, Prof. David Gozal, and Dr. Wei Li of Marshall University, conducted a study published in Frontiers in Immunology that uncovers a biological pathway through which SARS-CoV-2 may leave a lasting imprint on lung health.
Clinicians have long observed that many COVID-19 survivors develop interstitial lung fibrosis, a condition marked by scarring of lung tissue and known to increase cancer risk. Until now, however, the mechanism connecting viral infection to tumor development has remained unclear.
“The key question was whether the virus itself, particularly its spike protein, could set the stage for cancer,” the researchers said.
To investigate this, the team combined large-scale human data with mechanistic biological analysis.
Using the TriNetX global health database, researchers analyzed more than 166,000 patients, carefully matching cohorts demographically to isolate the effects of COVID-19.
Key findings include:
- COVID-19 survivors showed a significantly increased (albeit small) risk of lung cancer
- The risk was especially pronounced among current smokers
- Relative risk increased by 22%, with a hazard ratio of 1.50 (P < .001)
- Oral and bladder cancer risks were not increased (suggesting a specific predilection of the virus to affect the lungs).
“These findings suggest that COVID-19 is not only an acute illness, but may also have long-term implications for lung cancer risk, ” the researchers noted.
At the center of the newly identified pathway is an enzyme called thymidine phosphorylase (TYMP), which appears to play a critical role in linking viral-induced lung injury to tumor development.
The study found that activation of TYMP is associated with:
- Increased lung inflammation and tissue damage
- Enhanced fibrosis and collagen deposition
- Activation of STAT3, a well-known cancer-promoting signaling pathway
- A shift toward a tumor-supportive immune environment
“This suggests that TYMP doesn’t just influence tumor growth—it reshapes the entire immune environment of the lung in ways that can promote cancer,” the researchers explained.
Further analysis showed that the SARS-CoV-2 spike protein alters the processing of ACE2, the receptor the virus uses to enter lung cells, generating smaller fragments consistent with increased tissue turnover and damage.
Together, these findings outline a potential cascade:
Spike protein → lung injury → TYMP activation → STAT3 signaling → fibrosis and immune remodeling → tumor development
“This work provides a biological framework that helps explain emerging clinical observations since the pandemic began,” the researchers said. “While the absolute risk for any individual remains modest, the population-level implications are significant, particularly for individuals with existing risk factors such as smoking.”
Encouragingly, the study also points toward new therapeutic possibilities.
“By identifying TYMP as a central driver, we open the door to targeted strategies aimed at reducing long-term lung damage,” the researchers added. “Inhibiting this pathway could represent a novel approach not only for cancer prevention, but also for limiting fibrosis and chronic lung disease following viral infection.”
As the world continues to move from pandemic response to long-term recovery, understanding the hidden biological consequences of SARS-CoV-2 is becoming increasingly important.
“This study highlights both a potential risk and an opportunity,” the researchers concluded. “With deeper understanding comes the ability to intervene earlier and more effectively.”
The research paper titled “Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development” is now available in Frontiers in Immunology and can be accessed at
Researchers:
Cayleigh Wallace, Alex Gileles-Hillel, Amelia Cox, David Gozal, Wei Li, Hong Yue
Institutions:
1. Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, United States
2. Pediatric Pulmonology & Sleep, Department of Pediatrics, Hadassah Medical Center, and Faculty of Medicine, The Hebrew University, Jerusalem, Israel
3. Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, United States