Improving cancer therapy strategies via cellular stress and immune modulation

Despite significant progress in molecularly targeted and immune-based therapies, metastatic and chemoresistant cancers continue to exhibit poor clinical outcomes. This dissertation investigates two distinct therapeutic strategies designed to overcome tumor resistance and improve therapeutic efficacy. The first component of this work focuses on the small molecule ErSO, which induces cell death through hyperactivation of the unfolded protein response (UPR). Preclinical studies in osteosarcoma (OS), chondrosarcoma (CS), and Ewing sarcoma (ES) demonstrated potent ErSO mediated cytotoxicity and anti-metastatic activity, significantly extending survival even in late stage, chemoresistant models. Mechanistic analyses revealed that ErSO activity is independent of estrogen receptor alpha (ERα) but critically dependent on plasma membrane-localized TRPM4 which induces ATF6-mediate cell death. Immunohistochemical analysis of human OS tissues confirmed that TRPM4 is widely expressed, suggesting that a substantial subset of bone cancer patients may be responsive to ErSO-based therapy. The second component examines cannabidiol (CBD) as an immune microenvironment modulator and its interaction with anti-PD-1 checkpoint therapy in lung cancer. Although CBD broadly impairs functional immune activity under stimulatory conditions, its combination with anti-PD-1 antibody significantly reduced tumor burden in vivo compared with either monotherapy. Transcriptomic analysis revealed that CBD selectively decreased regulatory T cell (Treg) activity, improving the CD8+/Treg balance and enhancing antitumor immunity. These findings suggest that under certain conditions, CBD can refine rather than impair immune checkpoint therapy by selectively mitigating pro-tumor immune suppression. Collectively, this dissertation establishes two distinct therapeutic avenues: 1) TRPM4-mediate ErSO cytotoxicity for treating advanced bone cancers, and 2) CBD-driven immune modulation to potentiate checkpoint blockade in lung cancer.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Comparative Biosciences

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Lee, Yoongyeong

Contributors dc:contributor

• Fan, Timothy M
• Hergenrother, Paul J
• Spinella, Michael J
• Ko, CheMyong
• Wang, Bo

• Bone cancer
• Lung cancer
• ErSO
• TRPM4
• UPR
• CBD
• anti-PD-1

Statement dc:rights

• Copyright 2025 Yoongyeong Lee

Language dc:language

en

Handle dc:identifier

https://hdl.handle.net/2142/132761

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132761