Song Hongjian, Tong Zhichao, Xie Guixiang, Li Yaowei, Zhao Yubo, Fan Fengpu, Yang Zongzheng, Shi Qing, Zhang Qian, Wen Feng, Meng Hongxue, Li Haonan, Guo Pengyu, Hou Dayong, Zhang Zhenwei, Yin Zhihao, Liu Ziyi, Wang Jianwei, Zhang Peng, Dai Peng, Li Changfu, Teng Lichen, Xu Yangyang, Ding Dexin, Xu Tao, Li Jianzhang, Chen Yongsheng, Qiu Yu, Hu XiaoWei, Liu Wentao, Wu Liang, Nawroth Roman, Li Guibo, Su Hang, Deng Ziqing, Wang Ziqi, Wang Di, Xu Wanhai
NHC Key Laboratory of Molecular Probes and Targeted Theranostics, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, 150001, China.
Department of Urology, Harbin Medical University Cancer Hospital, Harbin, 150001, China.
Adv Sci (Weinh). 2025 Sep;12(33):e00216. doi: 10.1002/advs.202500216. Epub 2025 Jun 5.
Penile squamous cell carcinoma (PSCC) is a highly aggressive malignancy without effective treatment due to limited knowledge of its development and tumor microenvironment (TME). In this study, single-nucleus RNA sequencing (snRNA-seq) and high-resolution spatial transcriptomics are employed to comprehensively investigate the development trajectories and the TME. The results revealed that PSCC cells mimicked the differentiation and tissue organization of normal penile epithelium, independent of the human papillomavirus (HPV) infection status. Notably, a spatial subtype, Tum_1, appeared at early stage of tumor differentiation and in tumor-normal boundary regions. This subtype exhibited enhanced basal-like and stemness features and showed high LAMC2 expression, which activated laminin-integrin signaling via ITGA6/ITGB4, promoting tumor invasiveness. Furthermore, the results indicated that HPV-positive basal stem-like neoplasms dampened the immune function of T cells and macrophages, promoting an immunosuppressive environment that facilitates tumor progression. Supporting this, the patients with head and neck squamous cell carcinoma and lung squamous cell carcinoma who have high expression of HPV-positive Tum_1 signatures derived greater benefit from PD-1 blockade therapy. In summary, the findings provide a comprehensive spatial landscape of the PSCC TME and suggest potential treatment approaches targeting laminin-integrin interaction and immunotherapy, especially in HPV-positive patients.
阴茎鳞状细胞癌（PSCC）是一种侵袭性很强的恶性肿瘤，由于对其发展和肿瘤微环境（TME）的了解有限，目前尚无有效的治疗方法。在本研究中，采用单核RNA测序（snRNA-seq）和高分辨率空间转录组学来全面研究其发展轨迹和肿瘤微环境。结果显示，PSCC细胞模仿正常阴茎上皮的分化和组织构成，与人乳头瘤病毒（HPV）感染状态无关。值得注意的是，一种空间亚型Tum_1出现在肿瘤分化的早期阶段以及肿瘤与正常组织的边界区域。该亚型表现出增强的基底样和干性特征，并显示出高LAMC2表达，其通过ITGA6/ITGB4激活层粘连蛋白-整合素信号，促进肿瘤侵袭。此外，结果表明HPV阳性的基底干细胞样肿瘤抑制T细胞和巨噬细胞的免疫功能，促进有利于肿瘤进展的免疫抑制环境。支持这一观点的是，头颈部鳞状细胞癌和肺鳞状细胞癌患者中HPV阳性Tum_1特征高表达者从PD-1阻断治疗中获益更大。总之，这些发现提供了PSCC肿瘤微环境的全面空间图谱，并提出了针对层粘连蛋白-整合素相互作用和免疫治疗的潜在治疗方法，特别是在HPV阳性患者中。
