Abstract The immune system puts immense selective pressure on tumors to evolve mechanisms to avoid immune mediated cell death during tumorigenesis. Ultimately, these evolved tumor cells fuel the aberrant growth that leads to metastasis and patient mortality. Immunotherapies have been breakthrough treatments for certain tumor types highlighting just how life-changing reinvigorating the immune system can be in the battle against cancer. Unfortunately, current immunotherapies do not work for all patients and tumor types so we must identify new strategies that can turn non-responding patients into potent responders. To identify candidate drug targets whose inhibition can increase anti-tumor immunity (ATI), we utilized in vivo CRISPR screens in syngeneic mouse breast (BC) cancer models. The results from these screens revealed that inhibition of protein UFMylation, a ubiquitin-like post-translational modification pathway that is most known for its role in promoting protein translational fidelity, results in tumor cell death only in the presence of a fully functioning immune system. We have identified that loss of UFMylation can alter inflammatory gene expression to remodel the tumor microenvironment, promote antigen processing and presentation through the regulation of MHC class I protein levels, and render tumor cells more sensitive to killing by T cells. Using orthotopic in vivo tumor models that fail to respond to immunotherapies, we demonstrate that combining UFMylation inhibition with immune checkpoint blockade leads to potent ATI and a reduction in tumor growth. These data identify protein UFMylation as a drug target whose inhibition generates an anti-tumor immune response in tumors that fail to respond to immunotherapies. Citation Format: Ciara J. Miller, Jackson P. Riffee, Danielle R. Cook, Timothy D. Martin. Targeting the UFMylation pathway to promote immunotherapy response of breast cancers 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 7948.
Miller et al. (Fri,) studied this question.