Despite both being keratinocyte-derived skin cancers, basal cell carcinoma (BCC) responds much less robustly to immunotherapy than cutaneous squamous cell carcinoma (CSCC). The pathologic complete response rate to perioperative PD-1 inhibition in BCC is only 23%, less than half the 51% seen in CSCC, highlighting their distinct immunobiology.

For high-risk patients, oral acitretin has the strongest evidence for preventing skin cancers, with 30-50% efficacy. This is significantly higher than the debatable 20% efficacy of nicotinamide (Vitamin B3). Topical treatments like retinoids are considered ineffective for this purpose.

Though typically contraindicated, checkpoint inhibitors can be used for transplant recipients with advanced skin cancer. This requires shared decision-making, collaboration with the transplant team, and a specific protocol involving high-dose pulse steroids to mitigate the high risk of allograft rejection.

Clinicians should not treat all immunosuppression as a monolithic high-risk factor for skin cancer. Recent data show that lymphoproliferative disorders like chronic lymphocytic leukemia (CLL) pose a much greater risk for aggressive CSCC than many modern solid organ transplant medication regimens.

Contrary to the common assumption that metastatic disease is the primary cause of cancer-related death, a large international study on CSCC found that two-thirds of patients died from local-regional uncontrolled progression. This highlights the critical importance of effective local control strategies.

Nonmelanoma skin cancers' sensitivity to checkpoint inhibitors is due to high tumor mutational burden (TMB) caused by chronic UV light damage. This high TMB creates numerous neoantigens, which the immune system can effectively target once immunotherapy reverses immune suppression.

Patients receiving systemic immunotherapy for advanced skin cancer are still at high risk for developing new, low-risk primary skin cancers. Medical oncologists should not act as default dermatologists; ongoing co-management is crucial to identify and treat these new lesions while the patient is on systemic therapy.

The high efficacy of checkpoint inhibitors in cutaneous squamous cell carcinoma is enabling a "de-escalation" strategy. Upfront systemic therapy can be so effective that it eliminates the need for subsequent morbid local treatments like extensive surgery or radiation, a major benefit for elderly patients.

CLL-associated immunosuppression dramatically increases the risk and aggressiveness of skin cancers. This risk is not mitigated by novel therapies, and in some cases, the secondary skin malignancy can become a greater threat to a patient's life than their underlying CLL.