Abstract Radiation Therapy (RT) is one of the most common treatments for patients with solid tumors, administered to over 50% of patients. Failure of tumor control following RT, however, is a significant clinical challenge. In the present study, we identify a suite of novel proteins as radiation-inducible surface proteins across a variety of cancers, including breast and non-small cell lung cancers. Specific proteins characterized act as enzymes which deplete metabolic substrates, thus altering both the tumor microenvironment (TME) as well as cell intrinsic function. Using cell-surface capture mass spectrometry, bulk-RNA sequencing, fluorescence spectrometry, and cytometry by time of flight (CyTOF), we comprehensively characterize our target upregulation following RT, both as a surface protein and the enzymatic consequence of perturbation. To increase induction of surface expression, we evaluated combinatorial strategies of RT with small molecules and other soluble factors. These combinations significantly increased expression in vitro in both mouse and human non-small cell lung cancer cell lines. Additionally, in vivo, tumor-targeted RT/combination treatment significantly upregulated our protein of interest on tumor cells, as well as on a subset of macrophages and fibroblasts. Functional investigation suggests these macrophages and fibroblasts may have an immunosuppressive role within the TME. Leveraging these findings, we developed directed therapies, including antibody-drug conjugates (ADCs) and antigen-specific chimeric antigen receptor (CAR) T cells, to ablate both tumor and immunosuppressive cells with increased levels of the target, providing a more conducive combinatorial therapy to control tumors. In conclusion, we have identified and characterized a radiation-inducible therapeutic target, providing framework for reprogramming the TME and improving treatment efficacy. Citation Format: Courtney M. Tamaki, Maxwell Foisey, Charlotte Chen, Nam Woo Cho, . Leveraging radiation inducible surface protein targets for tumor microenvironment reprogramming 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 2835.
Tamaki et al. (Fri,) studied this question.