Xenograft tumors and TME recapitulated spontaneous human cSCC, facilitating in vivo CRISPR screens that identified an essential tumorigenic function for TSK-enriched integrin signaling genes ITGB1, FERMT1, and CD151. Together, these results uncover cSCC spatial heterogeneity, highlight potential intercellular signals controlling the positioning and states of associated cell types, and serve as a resource for further investigation of tumor and immune dynamics. Here, FERMT1 is linked to neoplasm.