Single-cell profiling reveals sustained immune infiltration, surveillance, and tumor heterogeneity in infiltrative BCC.

Infiltrative basal cell carcinoma (iBCC) is a particularly aggressive subtype of BCC that tends to progress and recur after surgery, and its malignancy is closely related to the tumor microenvironment. Here, we performed a comprehensive single-cell transcriptome analysis to profile 29,334 cells from iBCC and adjacent normal skin (ANS). We found active immune collaborations enriched in iBCC. Specifically, SPP1CXCL9/10 Macrophage1 had strong BAFF signaling with plasma cells, and T follicular helper-like cells highly expressed B-cell-chemokine CXCL13. Heterogeneous proinflammatory SPP1CXCL9/10 Macrophage1 and angiogenesis-related SPP1CCL2 Macrophage1 were identified within the TME. Interestingly, we found an upregulation of MHC-I molecules in fibroblasts in iBCC compared to ANS. Moreover, MDK signals derived from malignant basal cells were markedly increased, and their expression was an independent factor in predicting the infiltration depth of iBCC, emphasizing its role in driving malignancy and remodeling the tumor microenvironment. Additionally, we identified differentiation-associated SOSTDC1IGFBP5CTSV malignant basal subtype 1 and epithelial-mesenchymal transition-associated TNCSFRP1CHGA malignant basal subtype 2 cells. The high expression of malignant basal 2 cell markers was associated with the invasion and recurrence of iBCC. Altogether, our study helps elucidate the cellular heterogeneity in iBCC and provides potential therapeutic targets for clinical research.