Princeton researchers have resolved a decades-old mystery in cancer biology: vitamin A both fuels and undermines the immune response to tumors. Now they’ve built the first drugs to shut down the harmful side—without losing the benefits.
For years, the oncology community was stuck in an uncomfortable stalemate. Some studies suggested that vitamin A and its derivatives could boost the immune system’s ability to fight cancer; others showed precisely the opposite. Nobody could reconcile the contradictory data, and the controversy quietly stalled an entire line of research. Then a team at the Princeton branch of the Ludwig Institute for Cancer Research, led by molecular biologist Yibin Kang with key contributions from graduate student Cao Fang and former lab member Mark Esposito, decided to reframe the question entirely. Instead of asking whether retinoic acid helps or hurts the fight against cancer, they asked: how and when does it do each?
Their answer, published across two landmark papers in Nature Immunology and iScience, revealed a molecular double-cross. Retinoic acid—a derivative the body naturally produces from vitamin A—was activating a nuclear signaling pathway that suppresses the maturation of dendritic cells, the immune system’s essential scouts. Dendritic cells are responsible for detecting threats and rallying T cells to attack tumors, but when they remain immature, they fail to trigger a robust anti-tumor response, effectively handing cancer an invisibility cloak. Even worse, the same retinoic acid pathway undermined the potency of dendritic-cell vaccines, a promising and rapidly growing class of cancer immunotherapy. The team didn’t stop at diagnosis. Esposito and Kang designed a novel class of small-molecule inhibitors targeting ALDH1A, the enzyme responsible for producing retinoic acid inside the tumor microenvironment. Their lead compound, KyA33, selectively blocks the harmful immunosuppressive pathway while preserving retinoic acid’s beneficial roles elsewhere in the body—a precision approach that had resisted drug development for decades.
The commercial and clinical potential is significant. Esposito and Kang have founded Kayothera, a biotechnology startup, to bring ALDH1A inhibitors to clinical trials not only for cancer but also for diabetes and cardiovascular disease—conditions also driven by aberrant retinoic acid signaling. If the drugs prove safe and effective in humans, they could be combined with existing checkpoint inhibitors and cancer vaccines to dramatically improve patient outcomes, turning partially effective treatments into potent ones. For the millions of people worldwide currently receiving immunotherapy-based treatments, this research offers a concrete path to making those therapies work harder, by removing one of the immune system’s most insidious blind spots. It is a rare feat in cancer biology: not just understanding a paradox, but building a drug to exploit it.
5 Questions With Professor Yibin Kang
Q1: What first sparked your curiosity about this field, and was there a specific moment or experience that made you think, "This is what I need to work on"?
Y. Kang: My curiosity was shaped during my graduate training at Duke, where I studied virus–host interactions and became fascinated by how cells interact with and adapt to their environment. That experience pushed me to ask a more complex question: how do tumor cells hijack the host tissue microenvironment to enable metastasis? It felt like a natural progression from studying infection to studying cancer as a systemic, evolving process. That shift ultimately defined the direction of my research career.
Q2: Describe a moment in your research when you thought it might not work, and what kept you going.
Y. Kang: Our work on retinoic acid signaling went through several frustrating phases, especially during a period of time when results were inconsistent and difficult to reproduce. Cao, the graduate student leading the project, spent months troubleshooting before we realized that retinoic acid and its precursors’ light sensitivity and degradation in old media were introducing variability. What initially seemed like a technical nuisance turned out to be a key biological insight. That moment reframed the project and revealed how a metabolite (RA) could regulate dendritic cell maturation during vaccine generation.
Q3: If your research succeeds beyond your wildest expectations, how might it change everyday life for ordinary people 10-20 years from now?
Y. Kang: I believe we are moving toward a future where many cancers can be managed as long-term, controllable or curable diseases. By better understanding the drivers and vulnerabilities of cancer, we can develop new classes of drugs and combine them more effectively. This will likely involve integrating tumor-targeting therapies, microenvironment-modulating agents, and immunotherapy while blocking resistance and escape mechanisms. For patients, this could mean longer, healthier lives with more durable responses to treatment.
Q4: What's something about you or your path that might surprise people who only know you through your publications?
Many people may be surprised that I am deeply committed to endurance sports despite my busy life as a professor, cancer researcher and father of three children. I have completed multiple marathons, including the original six World Marathon Majors and two Ironman races, and I am currently training for Ironman Wisconsin. The discipline and resilience required for endurance training directly shape how I approach scientific challenges. In many ways, being an endurance athlete has made me a more persistent and focused scientist.
Q5: Who do you think about when you imagine the ultimate beneficiary of your work? Is there a specific person, community, or future generation that motivates you?
Y. Kang: I think about the many cancer patients I have encountered throughout my career,including colleagues, friends, and members of the broader community. I am also motivated by patient advocates and supporters who place their trust in scientific progress. Their experiences give a human face to what can otherwise feel like abstract research. Ultimately, I dedicate my work to improving outcomes and, one day, finding cures for these patients.
About Portal Innovations
Portal Innovations is a venture development platform that helps science-driven innovators build companies where they live. By providing seed capital, fully equipped lab space, and access to a global network built by founders who have taken startups public and raised over $1 billion, Portal gives researchers in emerging ecosystems a clear path from breakthrough to business. Deep university partnerships allow the team to identify top technologies early, attracting investors and corporate partners into new markets, while an in-house scientific team accelerates portfolio companies across strategy, data, and commercialization.
About Portal’s Research Spotlight Series
This summer, Portal Innovations is arriving in New Jersey as operator of a new incubator launching on the campus of The HELIX. To mark the occasion, Portal is spotlighting the extraordinary research happening at New Jersey's leading universities, including here at Princeton. The Research Spotlight Series is built on a simple conviction: that the breakthroughs shaping the future are already underway in university labs across the Garden State, and they deserve a wider audience.The goal: amplify outstanding science and champion New Jersey as an epicenter of innovation.
The Daily Princetonian’s editorial staff do not edit or otherwise review sponsored content.
Read More
