Single-cell aggrephagy landscape delineates intercellular communication of tumor microenvironment associated with ovarian cancer progression and immunotherapy.

Aggrephagy plays a pivotal role in ovarian cancer (OC) progression by clearing misfolded proteins. However, the functional role of aggrephagy within the tumor microenvironment (TME) remains elusive. Non-negative matrix factorization (NMF) was employed to analyze 43 aggrephagy-related genes (ARGs) on 65,820 single cells from scRNA-seq data of 12 samples (7 OC tissues and 5 normal tissues). The OC cohort from 9 public databases and TIDE-based immunotherapy scores were used to identify prognosis and immune response patterns of these TME cell clusters. Furthermore, the association between ARGs and CD8+ T cells was validated by the ID8 ovarian cancer mouse subcutaneous tumor model. Fibroblasts, T cells, macrophages and B cells identified from scRNA-seq of OC samples were subjected to biological process enrichment and classified based on ARGs expression patterns. Additionally, it revealed that ARGs may be significantly associated with clinical and biological characteristics of OC and pseudotime trajectories of major TME cell types. Bulk-seq analysis revealed that these aggrephagy-associated TME cell subsets were closely linked to the prognosis of OC patients and exhibited significant heterogeneity in predicting response to immunotherapy. Among them, CAF and CD8+ T cells showed particularly significant immune responsiveness. Notably, CellChat analysis revealed that aggrephagy-associated subtypes of TME cells engage in diverse and extensive interactions with tumor epithelial cells. Meanwhile, significant co-localization of TUBA1B with CD8+ T cells was observed in OC tissues from the mice model. This study is the first to delineate the role of aggrephagy regulators-mediated intercellular communication of the TME in regulating OC growth and antitumor immunomodulation.