鳞状细胞皮肤癌(cSCC)由于其高发病率和转移潜力而成为一个严重的公共卫生问题。它可能由光化性角化病变(AK)或原位癌基文氏病(AD)逐渐发展而来。在这个发展过程中，恶性角质形成细胞将皮肤深层成纤维细胞激活为促肿瘤的癌相关纤维细胞(CAFs)，它们的起源和形成仍然大部分是未知的。在这里，我们生成并分析了来自健康皮肤、基文氏病和鳞状细胞皮肤癌的男性供体的115,000多个单细胞转录组。我们的结果揭示了免疫调节和基质重塑的CAFs亚型，可能来源于促炎性和间充质的成纤维细胞。这些CAFs亚型在光化性角化病变中很少见，并与不同的细胞类型相互作用，建立了一个促肿瘤的微环境。这些发现是鳞状细胞皮肤癌特异的，在基底细胞癌中无法复制。我们的研究为皮肤深层CAF的潜在起源和功能提供了重要的见解，这对于特定靶向cSCC微环境将非常有益。©2023. Springer Nature Limited.

Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma, Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that may derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the potential origin and functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.© 2023. Springer Nature Limited.