Abstract PR004: Cancer cell intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis

Abstract The immunosuppressive tumor microenvironment (TME) plays a critical role in the therapeutic resistance to checkpoint inhibitors. However, precise factors that shape the immune contexture of the TME remain elusive. Here, we report that the Single-Stranded DNA Binding Protein 4 (SSBP4), a previously uncharacterized protein with no known function, suppresses intratumoral T cell activation by promoting excessive cholesteryl ester production from tumor cells. Overexpression of SSBP4 in tumor cells decreased T cell infiltration in the TME and accelerated tumor growth in a murine syngeneic tumor model. Conversely, genetic ablation of SSBP4 in tumor cells enhanced T cell infiltration, their activation and stunted tumor growth in a CD8+ T cell dependent manner. Furthermore, abrogation of SSBP4 dramatically enhanced the efficacy of anti-programmed cell death-1 (anti-PD-1) treatment. Mechanistically, SSBP4 expression promoted a concerted upregulation of cholesterol synthesis genes, leading to increased production of cholesteryl esters in tumor cells. In vitro studies showed that the cholesteryl esters released by SSBP4-expressing tumor cells directly suppressed CD8+ T cell activation and inhibited the expression of granzyme B and perforin. Together, we identify SSBP4 as a cancer cell intrinsic regulator of cholesterol biosynthesis that critically contributes to tumor immune evasion. Citation Format: Peiqi Ou, Ittai Eres, Junjie Zhao, Jaehak Oh, Chia-Jung Han, Chi-Ming Li, Andrew Rankin, Rajkumar Noubade, Xin Yu. Cancer cell intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr PR004.