Abstract
The resistance of tumors to immune checkpoint inhibitors (ICI) may be intricately linked to cellular senescence, although definitive clinical validation remains elusive. In this study, comprehensive pan-cancer scRNA-seq analyses identify fibroblasts as exhibiting the most pronounced levels of cellular senescence among tumor-associated cell populations. To elucidate this phenomenon, a fibroblast senescence-associated transcriptomic signature (FSS), which correlated strongly with protumorigenic signaling pathways and immune dysregulation that fosters tumor progression, is developed. Leveraging the FSS, the machine learning (ML) framework demonstrates exceptional accuracy in predicting ICI response and survival outcomes, achieving superior area under curve (AUC) values across validation, testing, and in-house cohorts. Strikingly, FSS consistently outperforms established signatures in predictive robustness across diverse cancer subtypes. From an integrative analysis of 17 CRISPR/Cas9 libraries, CDC6 emerges as a pivotal biomarker for pan-cancer ICI response and prognostic stratification. Mechanistically, experimental evidence reveals that CDC6 in tumor cells orchestrates fibroblast senescence via TGF-β1 secretion and oxidative stress, subsequently reprogramming the tumor microenvironment and modulating ICI response. These findings underscore the translational potential of targeting fibroblast senescence as a novel therapeutic strategy to mitigate immune resistance and enhance antitumor efficacy.