The success of immunotherapy in neoadjuvant and adjuvant settings has rendered the traditional, sequential referral model (dermatologist to surgeon to oncologist) obsolete. Optimal care now demands an integrated, team-based discussion among all specialists *before* the first treatment decision is made to determine the best sequence and timing.

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.

When debating immunotherapy risks, clinicians separate manageable side effects from truly life-altering events. Hypothyroidism requiring a daily pill is deemed acceptable, whereas toxicities like diabetes or myocarditis (each ~1% risk) are viewed as major concerns that heavily weigh on the risk-benefit scale for early-stage disease.

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.

The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.

Instead of a rigid, pre-defined treatment plan, clinicians are adopting a "response-determined" approach for cutaneous squamous cell carcinoma. A tumor initially deemed unresectable can become operable after just one or two doses of immunotherapy, requiring dynamic, ongoing collaboration between surgical and medical oncology teams to adjust the plan.

For patients who previously received immunotherapy (IO), a recurrence more than 12 months after completing treatment makes re-challenging with an IO agent a reasonable option. The likelihood of benefit is lower if the recurrence is within 6-12 months and minimal if under 6 months.

Data shows that patients who permanently stopped ipilimumab due to immune-related side effects still had exceptionally good outcomes. This gives clinicians confidence to manage toxicity by discontinuing the CTLA-4 inhibitor portion of the regimen while continuing nivolumab, without fearing a loss of efficacy.

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.