Abstract 900: Melanoma immune escape controlled by cancer cell-intrinsic STING signaling is linked to MHC-I suppression

Abstract Background: A crucial aspect of anti-tumor immunity is the infiltration of cytotoxic CD8+ T cells, which eliminate tumor cells by recognizing tumor antigens presented on major histocompatibility complex (MHC) class I molecules. The innate immune pathway regulated by Stimulator of Interferon Genes (STING) plays a significant role in modulating tumor immunity, and pathway activation is evident to impact T cell priming. In cancer cells, genomic instability leads to the accumulation of cytosolic DNA, activating the STING pathway and triggering a cytokine-driven immune response, which supports tumor control. However, to evade immune detection cancer cells continuously evolve mechanisms to evade immune recognition, such as downregulating MHC-I surface expression, thereby reducing the efficacy of CD8+ T cell-mediated cancer cell elimination. Methods: We utilized a syngeneic mouse model of the murine YUMM.G/YUMMER.G melanoma cells that present high or low somatic mutational burden (SMB), along with a cohort of human melanoma patient-derived cell lines. We investigated the modulating role of cancer cell-intrinsic STING signaling in tumor immunity, focusing on its impact on antigen presentation and immune cell infiltration under varying levels of SMB both in vitro and in vivo. Results: We observed that cancer cell-intrinsic STING signaling strongly associates with MHC I expression in our murine melanoma models. Similar correlations were found in a large group (n=76) of human melanoma patient-derived cancer cell lines. Our in vivo tumor models demonstrated that loss of STING expression significantly affected tumor control in melanoma models with high SMB. Notably, high SMB melanoma tumors deficient in STING expression escaped immune control by reducing infiltration and activation of cytotoxic CD8+ T cells. Conversely, STING depletion in low SMB melanoma cells had limited impact. Conclusion: Our findings advocate that STING expression status in melanoma plays a critical role in determining tumorigenicity, with its influence being dependent on the somatic mutational burden of the cancer cells. This highlights the potential of STING expressions within cancer cells as a critical factor for tumor immunogenicity and should be considered as an exploratory biomarker in immunotherapy settings combined with tumor mutational burden. Citation Format: Lea Skovmand Jensen, Anne Weiss, Arianna Draghi, Shawez Khan, Aida Solhøj Hansen, Anders Etzerodt, Bent Winding Deleuran, Marco Donia, Martin Roelsgaard Jakobsen. Melanoma immune escape controlled by cancer cell-intrinsic STING signaling is linked to MHC-I suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 900.