Integrative multi-omics and machine learning reveals the spatial niche distribution and role of CYP27A1TAMs in immunotherapy response in non-small cell lung cancer.

[BACKGROUND] The response rate to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) varies significantly among individuals. Cancer-associated macrophages (TAMs) are key components of the tumor immune microenvironment (TIME), influencing tumor proliferation, metastasis, immune cell recruitment, and activation through diverse mechanisms. Their high heterogeneity, particularly in the context of immunotherapy, warrants further investigation.

[METHODS] We integrated single-cell and spatial transcriptomic data from the same patients using ISCHIA to construct nine spatial niches(local cellular communities). The composition of these niches was compared across different spatial regions and between samples with varying ICB treatment responses. CYP27A1TAMs, identified as critical in ICB-responsive groups, were validated through external cohorts, immunohistochemistry, immunofluorescence, and experiments.

[RESULTS] Spatial niche analysis revealed that niche 9, which was enriched with effector cells, was found exclusively in ICB responders. CYP27A1TAMs were a key component of this niche, recruiting CD8T cells via antigen presentation and chemokine secretion, thereby improving patient prognosis. Based on this, we developed an accurate prognostic model. Following ICB treatment, these macrophages exhibited further activation of LXR and enhanced anti-apoptotic capabilities. and morphological experiments demonstrated that CYP27A1TAMs effectively suppressed tumor growth and increased CD8T cells infiltration in the TIME.

[CONCLUSION] This study highlights the importance of spatial niches in understanding the TIME of NSCLC and predicting ICB responses. CYP27A1TAMs and their downstream LXR pathway provide a novel research direction for exploring potential biomarkers for personalized NSCLC management.