Abstract Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by indolent growth but a high rate of metastasis, with approximately 40-60% of patients developing distant disease. Systemic therapies, including immune checkpoint inhibitors (ICIs), have shown minimal efficacy, and multiple clinical trials have failed to identify effective treatments for recurrent or metastatic ACC. In previous work, we profiled the ACC immune microenvironment using multiplex immunofluorescence (mIF) and found that ACCs are “cold” tumors, with scarce tumor-infiltrating lymphocytes (TILs) and uniformly low expression of B2M and HLA class I across nearly all analyzed samples in our cohort of 24 ACCs. Only metastatic lesions displayed focal HLA class I expression. Spatial transcriptomic analysis revealed that these focally positive regions were associated with an interferon-γ-driven transcriptional program. Short-term ex vivo treatment of ACC tissues with interferon-γ or a STING agonist strongly upregulated HLA class I, B2M, and PD-L1, suggesting that immune visibility of ACC can be pharmacologically restored. However, using surrogate cell lines (given the lack of established ACC cell lines), we observed that STING activation induced a negative feedback loop leading to suppression of STING signaling pathway with reduced STING, IRF3 and TBK1 expression after 24 hours. Co-treatment with a range of agents - including proteasome and lysosome inhibitors, kinase pathway inhibitors, epigenetic modifiers, and modulators of NF-κB or PI3K/AKT signaling - did not prevent this feedback inhibition. Clinically, one ACC patient treated with a combination of a STING agonist dazostinag and pembrolizumab over nine months showed a ∼70% reduction in tumor burden, while other patients experienced stable or progressive disease. One hypothesis is that differential activation of the STING feedback mechanism may underlie these varied clinical responses. These findings indicate that while ACC cells retain the machinery to upregulate antigen-presentation pathways, intrinsic mechanisms of STING pathway repression may limit the durability of immunostimulatory responses, underscoring the need for strategies to sustain interferon signaling in ACC. Ongoing work focuses on identifying strategies to overcome this feedback inhibition and on testing alternative agents capable of enhancing antigen presentation without triggering the same suppressive cascade, with the goal of developing more durable immunostimulatory therapies for ACC. Citation Format: Annie Li, Samantha E. Flynn, Prinjali Kalyan, Dawn R. Mitchell, Chengzhou Gao, Edwin Zhang, Diane Yang, Ross D. Merkin, William C. Faquin, Daniel L. Faden, Xin Gao, Jong Chul Park, Lori J. Wirth, A. John Iafrate. STING pathway activation reveals feedback inhibition potentially limiting immunostimulatory response in adenoid cystic carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4299.
Li et al. (2026) studied this question.