Immune Checkpoint Blockade Therapy for Advanced Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients, Transplant Recipients, and Individuals with Hereditary Syndromes: A Narrative Review.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with incidence steadily increasing due to cumulative ultraviolet (UV) exposure, impaired immune surveillance, and chronic tissue damage. While most cases are effectively managed with surgical excision, a subset progress to locally advanced or metastatic disease, associated with high recurrence rates, limited curative options, and poor prognosis. The introduction of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has significantly altered the management of advanced cSCC. Cemiplimab and pembrolizumab are now established systemic therapies, producing durable responses in a proportion of patients. These outcomes reflect the typically high tumor mutational burden and immunogenic microenvironment of cSCC. However, therapeutic decision-making remains particularly complex in several high-risk populations, including solid organ transplant recipients at risk of allograft rejection, patients with chronic dermatologic disorders or non-healing wounds that predispose to carcinogenesis, and individuals with rare hereditary syndromes such as recessive dystrophic epidermolysis bullosa. These so-called challenging populations are frequently excluded from pivotal trials, resulting in limited evidence regarding efficacy, safety, and optimal treatment strategies. This review summarizes current evidence on the management of advanced cSCC in high-risk and underserved patient groups, integrating trial data, real-world evidence, and contemporary guidelines. It also highlights key gaps in knowledge and outlines future directions, with particular focus on the interplay between host immune status, tumor biology, and therapeutic response.