Pan-cancer characterization of cellular senescence reveals its inter-tumor heterogeneity associated with the tumor microenvironment and prognosis.

Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.