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.
皮肤鳞状细胞癌（cSCC）是第二常见的皮肤恶性肿瘤，其发病率因累积性紫外线暴露、免疫监视功能受损及慢性组织损伤而持续上升。虽然多数病例可通过手术切除有效控制，但仍有部分进展为局部晚期或转移性疾病，具有高复发率、治疗手段有限及预后不良的特点。针对PD-1/PD-L1轴的免疫检查点抑制剂（ICIs）的应用显著改变了晚期cSCC的治疗格局。西米普利单抗和帕博利珠单抗已成为标准全身治疗方案，能使部分患者获得持久应答。这些疗效与cSCC通常具有的高肿瘤突变负荷及免疫原性微环境密切相关。然而，在若干高危人群中治疗决策仍尤为复杂，包括面临移植物排斥风险的实体器官移植受者、存在慢性皮肤病或易致癌的不愈合伤口的患者，以及隐性营养不良性大疱性表皮松解症等罕见遗传综合征患者。这些所谓"挑战性人群"常被排除在关键临床试验之外，导致关于疗效、安全性及最佳治疗策略的证据有限。本综述整合临床试验数据、真实世界证据及现行指南，总结当前针对高危及医疗服务不足人群晚期cSCC治疗的证据，同时指出关键知识缺口并展望未来研究方向，特别关注宿主免疫状态、肿瘤生物学特性与治疗反应之间的相互作用。
肿瘤(癌症)患者之家