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In this study, single\u2010nucleus RNA sequencing (snRNA\u2010seq) and high\u2010resolution 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\u2013normal boundary regions. This subtype exhibited enhanced basal\u2010like and stemness features and showed high LAMC2 expression, which activated laminin\u2010integrin signaling via ITGA6\/ITGB4, promoting tumor invasiveness. Furthermore, the results indicated that HPV\u2010positive basal stem\u2010like 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\u2010positive Tum_1 signatures derived greater benefit from PD\u20101 blockade therapy. 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