Unveiling the Noncanonical Autophagy-Independent Role of ATG7 and ATG9B in Head and Neck Squamous Cell Carcinoma (HNSCC)

The role of autophagy in cancer remains elusive, and nontargeted autophagy inhibitors have limited therapeutic effects in HNSCC. Here, we systematically analyzed the correlation of autophagy-related genes in HNSCC through TCGA and single-cell sequencing data (GSE103322). ATG9B and ATG7 were found to have noncanonical autophagy-independent functions in HNSCC. Specifically, ATG9B was a protective factor in HNSCC patients through downregulating cancer cell EMT, and ATG7 was correlated with the immunosuppressive environment in HNSCC. Mechanistically, single-cell analysis revealed that ATG9B increased the epithelial phenotype of cancer cells but did not influence EMT signaling pathways. ATG7 was strongly correlated with elevated immunosuppressive checkpoints like PD-1, PD-L1, and CTLA4 in HNSCC. Further single-cell analysis and multiple immunofluorescence colocalization analyses indicated that ATG7 contributed to the high expression of PD-L1 in myeloid cells but not cancer cells. Collectively, our results revealed noncanonical autophagy-independent functions of autophagy-related genes. These results increase understanding of the intricacies of autophagy and may contribute to precision treatment using autophagy-targeted therapies.

Automated summary

The study reveals noncanonical autophagy-independent functions of autophagy-related genes ATG9B and ATG7 in HNSCC. ATG9B protects HNSCC patients by downregulating cancer cell EMT, while ATG7 is correlated with the immunosuppressive environment in HNSCC. These findings contribute to a better understanding of the intricacies of autophagy and may have implications for precision treatment using autophagy-targeted therapies.