Cumulative lifetime exposure to ultraviolet radiation from the sun is the single biggest cause of squamous cell carcinoma (SCC), the second most common skin cancer. UVB rays are the primary culprit, directly damaging the DNA inside skin cells in ways that can eventually trigger uncontrolled growth. But UV exposure isn’t the only path to SCC. A weakened immune system, certain chemical exposures, viral infections, and inherited genetic conditions can all play a role, sometimes in combination with sun damage and sometimes entirely on their own.
How UV Radiation Damages Skin Cell DNA
Your DNA contains ring-shaped molecular structures that readily absorb ultraviolet light, making it especially vulnerable to UV radiation. When UVB rays hit your skin, they cause neighboring building blocks in a DNA strand (called pyrimidine bases) to fuse together, forming abnormal structures known as dimers. These dimers distort the DNA strand and, if not repaired, introduce permanent mutations when the cell divides.
One gene that frequently picks up these mutations is TP53, a tumor suppressor gene that acts as a critical safety switch. Normally, the protein it produces detects DNA damage and either pauses cell division to allow repairs or triggers the damaged cell to self-destruct. When TP53 is knocked out by UV-induced mutations, that safety switch breaks. Damaged cells keep dividing instead of dying, accumulating more mutations with each round. In squamous cell carcinoma specifically, researchers believe the combination of a disabled TP53 gene and the activation of growth-promoting signaling pathways is what ultimately pushes cells toward cancer.
These mutations don’t happen overnight. SCC is driven by cumulative sun exposure over years and decades, which is why it most commonly appears on sun-exposed areas like the face, ears, scalp, hands, and forearms. That said, sunburns and blistering episodes also matter. Memorial Sloan Kettering Cancer Center notes that SCC most often develops in people who were exposed to UVB radiation, especially those who experienced sunburns or blistering. The damage from a single bad burn adds to the running total your skin cells are keeping.
Skin Tone and Individual Risk
The amount of melanin in your skin, the pigment that gives skin its color and filters UV rays, strongly influences your risk. People with lighter skin produce less melanin and absorb more UV radiation into their skin cells. Research using the Fitzpatrick skin phototype scale (a I-to-VI classification based on how skin responds to sun exposure) found that SCC risk increases with each step toward lighter skin, from type VI (the darkest, least burn-prone) to type I (the lightest, most burn-prone). The relationship is linear: each incremental decrease in skin type corresponds to a measurable jump in risk.
This doesn’t mean people with darker skin are immune. SCC can develop in anyone, and when it does occur in people with more melanin, it’s more likely to appear in areas not typically exposed to the sun, sometimes driven by causes other than UV radiation.
Immunosuppression and Organ Transplant
Your immune system plays a surprisingly large role in preventing skin cancer. Immune cells constantly patrol for abnormal cells and destroy them before they can grow into tumors. When that surveillance system is suppressed, skin cancers can take hold far more easily.
The starkest example comes from organ transplant recipients, who take medications to suppress their immune systems and prevent organ rejection. These patients face up to 100 times the risk of developing skin cancer compared to the general population, according to UCSF Health, and SCC is the type they develop most often. The risk is high enough that transplant patients typically need regular skin checks for the rest of their lives. Other forms of immunosuppression, including from blood cancers, HIV, or long-term use of immune-suppressing drugs for autoimmune conditions, also raise SCC risk, though generally not to the same degree as post-transplant immunosuppression.
Human Papillomavirus (HPV)
Most people associate HPV with cervical cancer, but a different branch of the virus family is linked to skin cancers. More than 220 HPV genotypes have been identified, and a group called beta-HPV predominates in skin tissue. While the connection between alpha-HPV strains and cervical cancer is firmly established, growing evidence points to beta-HPV as a contributor to cutaneous SCC, particularly in people whose immune systems are already compromised.
The virus likely works as a co-factor rather than a standalone cause. In immunosuppressed individuals, beta-HPV may interfere with the skin’s ability to repair UV-damaged DNA or may prevent damaged cells from self-destructing, giving UV-induced mutations a better chance of surviving and accumulating. This helps explain why transplant recipients, who are both immunosuppressed and often HPV-positive in their skin, face such dramatically elevated SCC rates.
Chemical and Environmental Exposures
Not all squamous cell carcinomas trace back to sunlight. Chronic exposure to inorganic arsenic, whether through contaminated drinking water or workplace contact, is a well-documented cause. Arsenic-related SCCs have a distinctive pattern: they tend to appear on parts of the body that don’t get much sun, including the palms, soles, and trunk. The Agency for Toxic Substances and Disease Registry notes that arsenic-associated skin cancers are frequently characterized by lesions spread across the entire body rather than concentrated on the head and neck like UV-driven cancers.
Chronic wounds and long-standing scars can also give rise to SCC. When skin is trapped in a cycle of repeated injury and healing over many years, the constant cell turnover increases the chance of mutations. These cancers, sometimes called Marjolin ulcers, can develop in old burn scars, non-healing ulcers, or sites of chronic inflammation. They tend to be more aggressive than UV-related SCCs because they often go unrecognized until they’re advanced.
Inherited Genetic Conditions
A small number of people carry inherited mutations that make them extraordinarily vulnerable to SCC. The most dramatic example is xeroderma pigmentosum (XP), a rare condition caused by mutations in genes responsible for repairing UV-damaged DNA. At least nine different genes have been linked to XP, all involved in the same DNA repair pathway. Because both copies of the affected gene must carry the mutation (an autosomal recessive pattern), the condition is rare, but its effects are severe.
People with XP are 10,000 times more likely to develop non-melanoma skin cancers, including SCC, compared to the general population. Most develop their first skin cancer before age 10. Without strict protection from UV radiation, they typically develop multiple skin cancers throughout their lives. XP illustrates just how central DNA repair is to preventing SCC: when the repair machinery works normally, it catches and fixes most UV-induced damage before it becomes permanent. When it doesn’t, virtually every exposure leaves a lasting mark.
How These Causes Work Together
SCC rarely results from a single factor acting alone. In most cases, it develops through the interaction of cumulative UV damage with one or more additional risk factors. Someone with fair skin who works outdoors and has a history of sunburns is accumulating DNA damage faster and repairing it less effectively than someone with darker skin and limited sun exposure. Add immunosuppression or HPV infection to that picture, and the risk climbs further.
This layering effect also explains why SCC becomes more common with age. Older adults have had more years of cumulative sun exposure, their DNA repair mechanisms work less efficiently, and their immune surveillance weakens naturally. The average age at diagnosis reflects decades of accumulated damage finally reaching a tipping point.
The Role of Sunscreen in Prevention
Because UV radiation is the dominant cause, consistent sun protection is the most effective way to reduce your risk. A randomized controlled trial published in The Lancet found that daily sunscreen use reduced the incidence of squamous cell carcinoma by 39% compared to no daily sunscreen use. Notably, the same study found no significant effect of sunscreen on basal cell carcinoma rates, suggesting that SCC is especially responsive to UV reduction strategies. Protective clothing, shade-seeking behavior, and avoiding peak sun hours work alongside sunscreen to lower cumulative exposure over a lifetime.