Could the very vitamin we trust to protect us be the reason cancer cells are outsmarting our immune defenses?

Story Overview

• Vitamin A byproduct may aid cancer in evading the immune system.
• Princeton researchers developed KyA33 to counteract this effect.
• KyA33 shows promise in enhancing immune response in preclinical trials.
• Findings could reshape cancer treatment and dietary guidelines.

Vitamin A’s Paradoxical Role in Cancer

Researchers at Princeton University, part of the Ludwig Institute for Cancer Research, have uncovered a startling paradox involving vitamin A. While traditionally believed to induce cancer cell death, a vitamin A derivative known as all-trans retinoic acid (RA) may actually help cancer hide from the immune system. The team discovered that RA reprograms dendritic cells (DCs) to promote tumor tolerance, weakening natural anti-cancer responses and hampering the efficacy of cancer vaccines.

This discovery sheds light on the long-standing puzzle of why clinical trials have shown high vitamin A intake correlating with increased cancer risk despite lab results suggesting anti-cancer potential. Tumors cleverly exploit the overexpression of ALDH1a3 enzymes to produce RA, suppressing T-cell activity in the tumor microenvironment while evading RA’s anti-proliferative effects on the cancer cells themselves.

Vitamin A may be helping cancer hide from the immune system https://t.co/eO4oxC6fGk

— inmunoes (@inmunoes) January 16, 2026

Introducing KyA33: A Promising Solution

In response to these findings, Princeton researchers developed a drug named KyA33. This innovative compound targets the RA production pathway by inhibiting the ALDH1a2/ALDH1a3 enzymes. Preclinical tests in mouse models of melanoma have shown that KyA33 can significantly boost immune responses and slow tumor growth. This breakthrough represents the first successful attempt to target the previously undruggable RA pathway, offering new hope for cancer immunotherapy.

KyA33 serves a dual role as both a vaccine enhancer and a standalone immunotherapy. It is poised to revive stalled cancer vaccines by restoring DCs’ ability to mature and effectively trigger anti-tumor immunity. This development has led to the formation of Kayothera, a biotech company focused on the clinical translation of ALDH1A inhibitors for cancer, diabetes, and cardiovascular diseases.

Historical Context and Implications

The journey to this discovery has been fraught with contradictions. Since the mid-20th century, vitamin A derivatives like RA have been studied for their potential to induce cancer cell differentiation or death. However, major clinical trials revealed that high vitamin A intake could increase cancer incidence and mortality. The recent findings by the Princeton team resolve this paradox by explaining how cancers exploit RA to suppress the immune system.

This breakthrough has significant implications for both cancer treatment and dietary guidelines. Short-term, KyA33 could enhance the efficacy of existing DC vaccines and serve as a standalone treatment. Long-term, it offers a novel approach to developing RA inhibitors for various diseases, potentially shifting perceptions of vitamin A from a health booster to a risk factor in certain contexts.

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Expert Insights and Future Directions

Experts in the field are optimistic about the potential of KyA33. Yibin Kang, the lead researcher, highlights the drug’s ability to solve a decades-old pharmacological challenge and establish preclinical proof for a new form of immunotherapy. Michael Esposito, another key figure in the research, points out that cancer cells exploit RA while losing their responsiveness to retinoids, underscoring the need to target this pathway specifically.

The development of KyA33 is a testament to the power of interdisciplinary collaboration, combining computational modeling and drug screening to achieve a breakthrough. As Kayothera prepares for clinical trials, the research community eagerly anticipates the results, which could redefine cancer treatment paradigms and inform new dietary and supplement guidelines worldwide.

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Sources:

ScienceDaily
UChicago Medicine
Ludwig Cancer Research
Ludwig Cancer Princeton