An immunosuppressive subtype of senescent tumor cells predicted worse immunotherapy response in lung adenocarcinoma.

ABSTRACT

Senescent tumor cells (STCs) can induce immunosuppression, promoting tumor progression and therapy resistance. However, the specific characteristics of immunosuppressive STC have not been thoroughly investigated. This study aimed to characterize and elucidate the immunosuppressive phenotype of STC in lung adenocarcinoma by employing single-cell and bulk transcriptomics, as well as serum proteomics profiling. We identified senescence-related genes specific to tumors and identified Cluster10 of STC as the immunomodulatory subtype. Cluster10 exhibited a distinct secretome dominated by cytokines such as CXCL1, CXCL2, and CXCL8 and showed activation of transcription factors associated with cytokine secretion, including NFKB1, RELA, and STAT3. Notably, Cluster10 demonstrated the highest degree of intercellular communication among all cell types, with interactions as LGALS9-TIM3 and MIF-CD74. Furthermore, Cluster10 showed significant associations with poor prognosis and diminished response to immunotherapy. Analysis of serum proteomics data from our in-house cohort identified CXCL8 as a potential marker for predicting immunotherapeutic outcomes.