Abstract Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumor-propagating cell states in squamous tumors, further work is needed to elucidate the broader landscape of intra-tumoral heterogeneity within LUSC. Here, we employed SOX2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover cell fate diversity within LUSC, identifying a KRT13+ hillock-like population of slower-dividing tumor cells characterized by immunomodulatory gene expression signatures. The tumor hillock-like state was conserved across multiple animal and human-derived models and was computationally predicted in the majority of human LUSCs as well as head and neck and esophageal squamous tumors. Analysis of the cellular origins of tumor hillock-like states indicated that lung club cells give rise to tumors with luminal hillock-like populations while basal-like tumor-propagating cells transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, KLF4 promoted the KRT13+ hillock-like state and contributed to resistance to oxidative stress and platinum-based chemotherapy in vitro. Together, these results provide molecular insights into the lineage plasticity underlying intratumoral heterogeneity within LUSC, offering potential avenues for developing therapeutic strategies.
Izzo et al. (2026) studied this question.