Cellular senescence is a stress-activated differentiation pathway that causes proliferation arrest governed by two powerful tumor suppressor pathways, USP28-TP53-CDKN1A and CDKN2A-RB. Senescent cells exhibit a pro-inflammatory secretory program termed the senescence-associated secretory phenotype (SASP) that is composed of chemokines, cytokines, growth factors, and proteases. SASP induction is independent of TP53 and RB function and its role in cancer has not been fully elucidated. We genetically targeted the master regulator of SASP, GATA4, and found that SASP functions as a non-cell autonomous tumor suppressor mechanism. We show that SASP is tumor suppressive in mouse models of cancer using both deletion and overexpression contexts. SASP-dependent tumor suppression requires the immune system, specifically CD8 cytotoxic T cells, to suppress tumor growth. Human tumors deficient in GATA4 have reduced lymphocyte infiltrates, indicating that human cancers may avoid immune infiltration by limiting SASP. Citation Format: Rupesh S. Patel, Rodrigo Romero, Anthony C. Liang, Emma V. Watson, Megan Burger, Peter M.K. Westcott, Kim L. Mercer, Roderick T. Bronson, Eric C. Wooten, Arjun Bhutkar, Tyler Jacks, Stephen J. Elledge. The role of the senescence-associated secretory phenotype in cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA17.