Senescence rewires microenvironment sensing to facilitate anti-tumor immunity

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance. SIGNIFICANCE Our work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity. ### Competing Interest Statement S.W. Lowe is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus Inc., PMV Pharmaceuticals, Faeth Therapeutics, and Constellation Pharmaceuticals. M. Egeblad. is a member of the research advisory board for brensocatib for Insmed, Inc, a member of the scientific advisory board for Vividion Therapeutics, Inc., and a consultant for Protalix, Inc. No potential conflicts of interest were disclosed by the other authors. None of these affiliations influenced the work conducted or analysis of data presented in this manuscript.