Princeton University, Ludwig Institute for Cancer Research and Kayothera, Inc. Announce Publication of Foundational Research in iScience Detailing Novel Approach to Drugging Retinoid Nuclear Receptor Pathway
PRINCETON, NJ, October 14, 2025 — A paper published today in the peer-reviewed journal iScience, co-authored by researchers from Princeton University, Ludwig Institute for Cancer Research Princeton Branch and Kayothera, Inc., describes the development of the first orally available antagonists of the retinoid nuclear receptor pathway. This groundbreaking research, “Development of retinoid nuclear receptor pathway antagonists through targeting Aldehyde Dehydrogenase 1A3 (ALDH1A3),” resolves a long-standing paradox about the role of retinoids in health and highlights a key risk to consumers of high-dose Vitamin A or retinol supplements.
It has long been known that consumption of excess retinoids, including high dose retinol (Vitamin A), results in dramatically elevated mortality due to increases in both cardiovascular disease and lung cancer. This finding has been replicated in large-scale randomized clinical trials across multiple countries. In contrast, the prevailing public wisdom is that Vitamin A and other retinoids promote heart health and suppress cancer. While the anti-cancer effects of retinoids are sometimes observed in laboratory models, beneficial effects of retinoid therapy have never been conclusively shown in patients with solid cancers. The newly published research from Princeton University reveals the mechanistic basis for this paradox by demonstrating that ALDH1A3 is overexpressed in diverse cancers to generate retinoic acid, the downstream metabolite of retinol that activates the retinoid nuclear receptor pathway. Secretion of retinoic acid then suppresses the body’s anti-tumor immune response. Meanwhile, retinoic acid-producing cancer cells lose responsiveness to retinoic acid signaling, explaining why retinoid treatment has no clear positive effect in solid cancer patients. These findings help explain the seeming contradiction between a decades-old hypothesis that retinoids are beneficial and the clinical observation that retinoids worsen health outcomes.
The retinoid nuclear receptor pathway has long been a challenging therapeutic target, with many large pharmaceutical companies attempting to create antagonists in the early 2000s but failing after years of effort. There are twelve classic nuclear receptor pathways, and, despite being discovered first, the retinoid nuclear receptor pathway is the only one that has not been successfully drugged. To overcome this challenge, the researchers developed a hybrid computational and high-throughput screening approach, followed by medicinal optimization, to create first-in-class, oral, and safe antagonists of ALDH1A3. These novel inhibitors both demonstrated potent anti-tumor immunotherapeutic activity in preclinical models and possessed an optimized drug development profile, positioning them as a potential new class of cancer immunotherapies.
“Our work addresses a decades-old controversy in retinoid biology and provides a clear mechanism by which ALDH1A3 drives disease,” said Yibin Kang, Ph.D., Lead Contact for the publication and a co-author. “By developing antagonists that safely inhibit this pathway, we are paving the way for a novel therapeutic approach to cancer that was not previously possible.”
Mark Esposito, Ph.D., first author of the paper and a co-founder of Kayothera, Inc., added, “This publication highlights the foundational science behind Kayothera and our unique approach to targeting this important pathway. It provides the biochemical validation for our drug development efforts and underscores the potential for our therapies to address significant unmet medical needs in oncology and cardiometabolic diseases.”
About the Publication
The paper is available online in the journal iScience. DOI: 10.1016/j.isci.2025.113675
Title: Development of retinoid nuclear receptor pathway antagonists through targeting Aldehyde Dehydrogenase 1A3 (ALDH1A3)
Authors: Mark Esposito, Cao Fang, Yong Wei, Alfonso Pozzan, Claudia Beato, Xiaoyang Su, Josiah E. Hutton III, Tavis Reed, Xiang Hang, Enrico D. Perini, Wen Wang, Xiaobing Cheng, Yan Pan, Jianshi Yu, Maureen Kane, Malini Manoharan, John Proudfoot, Ileana M. Cristea, and Yibin Kang.