Abstract B016: Pharmacologic inhibition of the Glucocorticoid Receptor synergizes with immunotherapy to prevent metastatic recurrence in pre-clinical models

Abstract Metastasis is the major cause of death for patients with solid cancer. Metastases arise from cancer cells that disseminate from the original tumors, survive systemic immune surveillance, and colonize new organs. As current therapies often fail to eradicate these Disseminated Tumor Cells (DTCs), immunotherapy holds immense promise to target undetectable DTCs and prevent metastatic recurrence. However, little is known about immune surveillance against DTCs during metastatic seeding. The investigation of cancer immune evasion has largely focused on the tumour mass, where a myriad of immune suppressive populations cooperate with cancer cells to block immunotherapy responses. DTCs, in contrast, persist outside of this protective microenvironment and thus need to evolve additional cell-autonomous mechanisms of immune evasion to survive. Developing effective immunotherapies against metastasis requires precise understanding of how tumor cells resist immune clearance upon dissemination. To address this question, we leveraged a visible fluorescent antigen and cognate CD8+ T cells in a Triple Negative Breast Cancer model of lung metastasis to profile immune-resistant DTCs. These studies uncovered heightened chronic stress hormone signaling through the Glucocorticoid Receptor (GR) in DTCs that evade immune attack. Suppression of GR activity in cancer cells drastically reduced metastasis despite having negligible effects on primary tumor growth, thus identifying GR as a protective mechanism that is specific to initial metastatic seeding. We found that GR activation directly protected DTCs from pan-cytotoxic lymphocytes, including both CD8+ T cells and Natural Killer (NK) cells. By engineering a niche labeling system to profile direct DTC-lymphocyte interactions in vivo, we discovered that GR activation in DTCs reduced interaction through the Fas-Fas Ligand (FasL) pathway. Mechanistically, GR represses the death receptor Fas on tumor cells to resist FasL-mediated killing by NK and T cells. This reveals Fas-FasL as a crucial pathway for DTC elimination, despite its minor role in primary tumors, highlighting that the immune system deploys distinct mechanisms of surveillance against DTCs. Further, we discovered the GR-Fas axis as a DTC-specific mechanism of immune evasion that provides widespread protection from pan-cytotoxic immunity. Pharmacologic inhibition of GR using the FDA-approved drug Mifepristone in combination with anti-PD1 immunotherapy drastically reduced DTC metastasis and extended mouse lifespan. These findings illustrate the unique features of cancer-immune interactions during disease progression, and highlight the distinct adaptations developed by vulnerable DTCs for immune resistance at this key stage of the metastatic cascade. Therapeutic strategies to prevent metastasis are lacking, and our findings suggest that there are opportunities to eliminate DTCs separately from treatments aimed at primary tumors. This work proposes GR inhibition as one promising combinatorial approach to target DTCs and reduce metastatic recurrence. Citation Format: Monica Cassandras, Xavier Sanchez, Lauren Hsu, Judith Agudo. Pharmacologic inhibition of the Glucocorticoid Receptor synergizes with immunotherapy to prevent metastatic recurrence in pre-clinical models [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B016.