NMSC Immunotherapy Guide IAR

In nonmelanoma skin cancer (NMSC), particularly cutaneous squamous cell carcinoma (cSCC), treatment selection has evolved with the integration of immune checkpoint inhibitors (ICIs) across multiple stages of disease. Current guidelines support a risk-adapted approach in which ICIs play a central role for patients with high-risk, locally advanced, or metastatic disease, as well as an emerging role in earlier treatment settings. For unresectable or metastatic disease, ICIs targeting the PD-1/PD-L1 pathway are the preferred systemic therapy, offering durable responses and a favorable tolerability profile compared with traditional approaches. Their use is supported by the underlying tumor biology of cSCC, which is characterized by a high tumor mutational burden driven by ultraviolet radiation exposure. This leads to increased neoantigen formation and enhanced tumor immunogenicity, making these tumors particularly responsive to immune modulation. In addition, upregulation of immune checkpoint pathways such as PD-1/PD-L1 contributes to immune evasion, providing a strong mechanistic rationale for checkpoint blockade. Beyond advanced disease, ICIs are increasingly being incorporated into neoadjuvant and adjuvant treatment strategies for high-risk, resectable NMSC. In the neoadjuvant setting, ICIs may reduce tumor burden, improve surgical outcomes, and, in some cases, enable less extensive resections. In the adjuvant setting, they are being explored to reduce the risk of recurrence following surgery, particularly in patients with high-risk pathologic features. These approaches reflect a shift toward earlier immune intervention in the disease course.