Konstantaraki Maria, Berdiaki Aikaterini, Neagu Monica, Zurac Sabina, Krasagakis Konstantinos, Nikitovic Dragana
Department of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece.
Dermatology Department, University Hospital of Heraklion, 71110 Heraklion, Greece.
Cancers (Basel). 2025 Apr 2;17(7):1212. doi: 10.3390/cancers17071212.
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME-through inhibition of ECM components, MMPs, or integrin signaling-may enhance immune responses and improve clinical outcomes.
默克尔细胞癌（MCC）是一种罕见但侵袭性强的神经内分泌皮肤癌，由默克尔细胞多瘤病毒（MCPyV）整合或紫外线（UV）诱导的突变驱动。在MCPyV阳性肿瘤中，病毒T抗原使肿瘤抑制因子pRb和p53失活，而病毒阴性的MCC则含有激活相似致癌途径的紫外线诱导突变。包括PI3K/AKT/mTOR和MAPK在内的关键信号级联反应支持肿瘤增殖、存活和抗凋亡。从组织学上看，MCC由具有神经内分泌特征、高有丝分裂率和坏死的小圆形蓝色细胞组成。肿瘤微环境（TME）在疾病进展和免疫逃逸中起核心作用。它由肿瘤相关巨噬细胞、调节性和细胞毒性T细胞混合组成，免疫检查点分子如PD-L1表达升高，形成免疫抑制微环境。TME中的细胞外基质（ECM）富含蛋白聚糖、胶原蛋白和基质金属蛋白酶（MMPs），促进肿瘤细胞黏附、侵袭以及与基质和免疫细胞的相互作用。ECM重塑和整合素介导的信号传导进一步促进免疫逃逸和治疗耐药性。尽管靶向PD-1/PD-L1的免疫检查点抑制剂在治疗MCC方面已显示出前景，但耐药性仍然是一个主要障碍。同时通过抑制ECM成分、MMPs或整合素信号传导来靶向TME的治疗策略可能会增强免疫反应并改善临床结果。
