Researchers at the Princeton University Branch of the Ludwig Institute for Cancer Research say they have identified a way a vitamin A–derived molecule can blunt the immune system’s ability to fight cancer. The molecule, called all-trans retinoic acid, appears to weaken natural anti-tumor immune responses and, in certain settings, can also reduce the impact of a promising type of cancer vaccine.
The findings, reported across two studies, help explain why vitamin A–related compounds (retinoids) have produced conflicting results in cancer research over the years. The work also led to experimental drug candidates designed to shut down the cellular signaling pathway activated by retinoic acid.
How retinoic acid can undermine cancer vaccines
In one study published in Nature Immunology, researchers led by Yibin Kang and graduate student Cao Fang focused on dendritic cells—immune cells that help initiate and direct immune attacks. The team found that retinoic acid produced by dendritic cells can reprogram these cells in a way that encourages tolerance toward tumors, making cancer harder for the immune system to recognize and eliminate.
This immune tolerance can significantly reduce the effectiveness of dendritic cell vaccines, a form of immunotherapy intended to “train” the immune system to target tumor-specific markers. The researchers also described the development and preclinical testing of a compound, KyA33, that blocks retinoic acid production in both cancer cells and dendritic cells. In animal studies, KyA33 improved dendritic cell vaccine performance and also showed potential as a stand-alone immunotherapy.
A strategy to shut down retinoid signaling
A second study, led by former Kang lab graduate student Mark Esposito and published in iScience, explored how to design drugs that inhibit retinoic acid production and, more broadly, disable retinoid signaling. Although retinoids have been studied for more than a century, attempts to safely block this pathway with drugs have repeatedly fallen short.
The team combined computational modeling with large-scale drug screening to identify compounds capable of targeting a pathway that had resisted drug development for decades. This approach helped produce the framework used to develop KyA33.
Why this matters for cancer immunotherapy
According to the researchers, the combined results show that retinoic acid can broadly dampen immune responses that are crucial for anti-cancer defense. They also argue that the new inhibitor strategy may finally provide a practical way to target retinoic acid signaling in cancer immunotherapy.
The enzymes behind the signal
Retinoic acid is produced by enzymes in the ALDH1A family. ALDH1A3 is often found at high levels in human cancer cells, while a related enzyme, ALDH1A2, can generate retinoic acid in certain dendritic cell subsets.
Once formed, retinoic acid activates receptors in the cell nucleus, triggering changes in gene expression. In the gut, this signaling is known to promote regulatory T cells (Tregs), which help prevent harmful autoimmune reactions. Until now, however, it was not clear how retinoic acid affected dendritic cells themselves.
Dendritic cells and the promise—and limits—of vaccines
Dendritic cells act as sentinels: they monitor tissues for threats, process fragments of abnormal proteins, and present these “antigens” to T cells, which can then seek out and destroy infected or cancerous cells.
Dendritic cell vaccines are typically made by collecting precursor immune cells from a patient’s blood and maturing them in the lab with antigens derived from the patient’s tumor. These prepared cells are then infused into the patient to provoke a stronger, more targeted anti-tumor response.
Even as scientists have become better at identifying tumor antigens, dendritic cell vaccines often underperform in clinical trials. The Princeton-led team investigated whether the vaccine manufacturing process itself might be part of the problem.
How vaccine preparation may trigger immune suppression
The researchers found that under conditions commonly used to produce dendritic cell vaccines, developing dendritic cells begin expressing ALDH1A2 and generate high levels of retinoic acid. The signaling triggered by retinoic acid then suppresses dendritic cell maturation—reducing their ability to activate strong anti-tumor immunity.
The effect may extend beyond dendritic cells. Retinoic acid released by these cells can also push the immune environment toward macrophages that are less effective at fighting cancer. As these macrophages accumulate, the overall impact of dendritic cell vaccines may decline even further.
Restoring immune activity with KyA33
In mouse experiments, blocking ALDH1A2—either genetically or with KyA33—restored dendritic cell maturation and improved their ability to stimulate immune defenses. Vaccines produced in the presence of KyA33 generated stronger, more targeted immune responses in melanoma models, delaying tumor formation and slowing progression.
When administered directly, KyA33 also acted as an immunotherapy on its own, reducing tumor growth by boosting anti-tumor immune activity.
Explaining the “vitamin A paradox” in cancer
The development of inhibitors that target ALDH1A2 and ALDH1A3 is notable because the retinoic acid pathway is one of the classic nuclear receptor signaling systems—and had remained the only one without successful pathway-blocking drugs.
The new work also helps explain why vitamin A has seemed to have contradictory relationships with cancer. In lab studies, retinoic acid can slow cancer cell growth or trigger cell death, supporting the idea that vitamin A may be protective. Yet large clinical trials and other evidence have linked high vitamin A intake with higher cancer risk (as well as cardiovascular disease) and increased mortality. High levels of ALDH1A enzymes in tumors have been associated with worse outcomes across multiple cancers.
The researchers propose that many tumors may produce retinoic acid but become less responsive to its direct anti-proliferative effects. Instead, the dominant impact may occur in the tumor microenvironment, where retinoic acid suppresses immune activity, including the function of T cells that would otherwise attack the cancer.
In support of this, the team reported that ALDH1A3 inhibitors triggered robust immune attacks against tumors in mouse models, suggesting the approach could become a powerful form of immunotherapy.
Next steps toward new treatments
The scientists say that safe, selective inhibition of retinoic acid nuclear signaling could open a new therapeutic path not only for cancer, but potentially for other diseases influenced by retinoic acid. Esposito and Kang have also launched a biotechnology company, Kayothera, with the goal of moving ALDH1A inhibitors toward clinical testing for cancer and other conditions, including diabetes and cardiovascular disease.
Research support
The Nature Immunology study was supported by the Ludwig Institute for Cancer Research and multiple philanthropic and research organizations. The iScience study received support from the Ludwig Institute for Cancer Research and additional foundations and scientific funding bodies.