Exploring cellular diversity in lung adenocarcinoma epithelium: Advancing prognostic methods and immunotherapeutic strategies

Abstract Immunotherapy has brought significant advancements in the treatment of lung adenocarcinoma (LUAD), but identifying suitable candidates remains challenging. In this study, we investigated tumour cell heterogeneity using extensive single‐cell data and explored the impact of different tumour cell cluster abundances on immunotherapy in the POPLAR and OAK immunotherapy cohorts. Notably, we found a significant correlation between CKS1B+ tumour cell abundance and treatment response, as well as stemness potential. Leveraging marker genes from the CKS1B+ tumour cell cluster, we employed machine learning algorithms to establish a prognostic and immunotherapeutic signature (PIS) for LUAD. In multiple cohorts, PIS outperformed 144 previously published signatures in predicting LUAD prognosis. Importantly, PIS reliably predicted genomic alterations, chemotherapy sensitivity and immunotherapy responses. Immunohistochemistry validated lower expression of immune markers in the low‐PIS group, while in vitro experiments underscored the role of the key gene PSMB7 in LUAD progression. In conclusion, PIS represents a novel biomarker facilitating the selection of suitable LUAD patients for immunotherapy, ultimately improving prognosis and guiding clinical decisions.