Overview

Lip cancer is a subset of oral cancer.¹ It is a relatively rare yet impactful condition, which usually starts in the thin and flat cells on the lower lip, with squamous cell carcinomas (SCCs) being the most common type of cell from which the cancer originates.¹ Individuals with fair skin and outdoor occupations are more prone to lip cancer due to long-term ultraviolet (UV) exposure from the sun.¹ Smoking and alcohol consumption are also traditional risk factors that are well-established for cancer.² 

There is, however, another, less talked about factor that can modulate someone’s risk of developing lip cancer – having a weakened immune system.³ Among organ transplant recipients and individuals with chronic autoimmune conditions, taking immunosuppressive medication is a necessary part of allowing the transplanted organ to function successfully.³ These drugs help to prevent the body from attacking itself whilst also minimising rejection.³ However, they also dampen the body’s natural tumour surveillance ability to identify and destroy abnormal growing cells, which makes it easier for pre-cancer and cancer cells to develop over time.⁴ 

Following transplantation, the risk of cancer increases by 2-3 times compared to the general population.¹ The lips are constantly exposed to the sun’s radiation and environmental damage. It is still often overlooked when it comes to sun protection, making them more vulnerable in people whose immune defences are already lowered, such as in transplant patients.³ As more people rely on immune-suppressing treatments, the intersection between immunomodulatory therapies and lip cancer is a growing concern for clinicians to protect those most at risk.¹ 

Mechanism of immunosuppression

The immune system is the body’s powerful way to protect us from viruses and bacteria, from superficial wounds, and, in our internal defence mechanism, from cancer.⁴ It patrols the body for cells that are growing or behaving irregularly, including potentially malignant cells. When these are found, the immune system usually acts quickly to destroy them before they can form a tumour.⁴ 

However, in immunosuppressed individuals, this protective system is compromised. Immunosuppression means that the immune system is deliberately weakened by suppressing T cells and B cells, which reduces the immune system’s ability to fight off cancer cells.⁴ After organ transplantation surgeries, ‘anti-rejection’ immunosuppressant drugs are provided to patients to stop the immune system from recognising the new organ as ‘foreign’ and mistakenly destroying the body’s own tissues to avoid rejection.³ 

However, they can also make matters worse as they can increase a person’s sensitivity to sunlight, which is especially concerning since UV radiation is already a known risk factor for lip cancer.³ This creates a dangerous combination: an impaired immune system, combined with sun exposure, exacerbates the chances of cancer.³ Therefore, while immunosuppressive therapy is necessary and life-saving for cancer patients, it comes with side effects and brings more opportunities for damaged cells to grow unchecked, increasing the probability of developing certain cancers.⁵ 

Immunosuppressive medication 

One of the most important jobs the immune system has is to act as a surveillance system to keep an eye out for cells that are growing out of control. Unfortunately, when the immune system is weakened and the natural monitoring is disrupted, it even changes how the body behaves at a cellular level.⁵ 

In people who are immunosuppressed, the long-term effects on cell health, DNA repair, and virus control can quietly tip the balance toward cancer progression as the system can no longer keep track of every abnormal cell.¹ Some commonly used immunosuppressive drugs are corticosteroids, azathioprine, and calcineurin inhibitors (cyclosporine), which are very effective at calming immune responses and can therefore also be used to treat autoimmune diseases.³ 

However, an issue with these maintenance medications is the DNA-damaging effects that may directly contribute to the onset of lip cancer. 

When the body processes azathioprine, it makes our skin cells more sensitive to sunlight, which can lead to the production of harmful substances that damage healthy cells from the inside out.¹ This may explain why people taking azathioprine are more likely to develop lip cancers.⁶ 

On the other hand, cyclosporine encourages cancer growth differently. This drug increases a protein that encourages the formation of new blood vessels, which can unintentionally feed a growing tumour, helping the cancer grow faster.¹ It can also get in the way of the body’s ability to fix damaged DNA, meaning that small errors in cells may go unchecked.¹ Over time, when these cells are not repaired properly, this build-up increases the chances that a cell will turn cancerous. 

Therefore, patients on long-term immunosuppressive drugs are more likely to develop lip cancer even on the inside of the lip, where there is minimal sun exposure.¹ This suggests that the biological connection between immunosuppression and these drugs does not just make the skin more sun-sensitive, but they also directly increase the risk of lip cancer by interfering with DNA and creating a tumour-friendly environment.⁴ 

Oncogenic viruses 

Although the causal relationship is still ambiguous, there is also growing evidence linking certain viruses to the onset of lip cancer.¹ Two of the well-established viruses for SCCs are: Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection, with particularly high-risk strains being HPV-16 and HPV-18.⁷ These viruses tend to affect the skin and mucous membranes which include the inside of the lip or where the skin meets the moist lip lining, so when an infection occurs in these regions the risk of lip cancer also seems to increase.²

In healthy individuals, these viruses are usually kept under control by the immune system.⁴ 

However, in people with a deteriorated immune system, such as after an organ transplant or from immunosuppressive therapy, these viruses can reactivate or linger in the body longer than they should, which affects how cells interfere with growth and division.¹ This leads to cancerous genetic mutations as they cannot clear infections effectively.⁴ 

HPV produces proteins that can disable tumour-suppressor genes, p53, which removes one of the body’s key defences against cancer. Therefore, these viruses add another layer of complications by creating more stress on cells that are already struggling to repair themselves, which explains the elevated lip cancer rates among immunosuppressed patients.⁷ 

Prevention and management 

For immunosuppressed people, preventing cancer means being proactive at reducing known risks and keeping a close eye on early warning signs. One of the most important steps is to protect the lips from UV radiation, especially for those taking azathioprine, which makes the skin more sensitive to sunlight.⁶ Using a broad-spectrum lip balm with SPF, wearing a wide-brimmed hat, and avoiding prolonged exposure to intense midday sun can all help reduce this risk.⁸ 

Another key area is to detect viral infections by scheduling regular oral screenings to spot signs of abnormal tissue growth before they become a bigger issue.⁸ Some individuals can also benefit from receiving an HPV vaccination.⁸ Furthermore, patients on immunosuppressants should also be regularly monitored. Adjusting the dosages of certain medications or even switching to alternatives that carry a lower risk for cancer should be considered accordingly.⁶ This should be carefully balanced against the need to protect the transplanted organ or to manage an autoimmune condition.¹ Self-checks are also valuable, as this is where patients are informed to observe any changes on or around the lips, such as persistent sores, lumps, and ulcers that do not heal.⁸ 

The prognosis for lip cancer is generally positive due to its visible symptoms and early detection.² In most cases, Mohs surgical technique, which removes the cancerous tissue layer by layer, can be done with minimal long-term cosmetic and functional impact by preserving as much healthy tissue as possible.⁹ In more advanced cases, chemotherapy and radiotherapy may be required.² 

Summary

Research has shown that people with weakened immune systems, such as those who have had organ transplants or are taking immunosuppressive drugs, face a markedly higher incidence rate of developing some cancer types, and lip cancer appears to be one of them. This is because the immune system, which normally helps destroy unusual cells before they become a danger to the body, becomes suppressed, and the protection is dampened. 

Understanding how immunosuppressive states contribute to carcinogenesis on the lips not only deepens our knowledge of the mechanisms of lip cancer but also highlights the importance of tailored screenings, preventive strategies, and smarter use of medication in vulnerable populations. Some drugs lower immune defences whilst damaging DNA and also make the skin more sensitive to sunlight, further increasing the risk. HPV and EBV viruses are harder to control in immunosuppressed individuals, allowing the virus to interfere with cell growth in ways that contribute to cancer. Ultimately, staying ahead of the problem and early detection are key to a successful outcome in the treatment of lip cancer.