T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis

Despite autophagy modulating tumor immunity in the tumor microenvironment (TME), the immunotherapeutic efficacy and potential mechanism of autophagy signature was not explicit. We manually curated an autophagy gene set and defined a pan-cancer autophagy signature by comparing malignant tissues and normal tissues in The Cancer Genome Atlas (TCGA) cohort. The pan-cancer autophagy signature was derived from T proliferating cells as demonstrated in multiple single-cell RNA sequencing (scRNA-seq) datasets. The pan-cancer autophagy signature could influence the cell-cell interactions in the TME and predict the responsiveness of immune checkpoint inhibitors (ICIs) in the metastatic renal cell carcinoma, non small cell lung cancer, bladder cancer, and melanoma cohorts. Metabolism inactivation accompanied with dysregulation of autophagy was investigated with transcriptomic and proteomic data. The immunotherapeutic predictive role and mechanism regulation of the autophagy signature was validated in an in-house cohort. Our study provides valuable insights into the mechanisms of ICI resistance.