In breakthrough papers from Nature Immunology and iScience, Ludwig Princeton researchers Yibin Kang and Mark Esposito reveal how all-trans retinoic acid (ATRA)—a vitamin A offshoot—lets tumors dodge destruction. Think of ATRA as a double agent: essential for vision and immunity in the gut, but hijacked by cancers via enzymes ALDH1a3 (in tumor cells) and ALDH1a2 (in dendritic cells, DCs). This creates "immune tolerance," where the body's defenders stand down, weakening natural attacks and even cancer vaccines.
Dendritic cells act like immune alarm systems—they snag tumor pieces, show them to T cells, and spark killer squads. But during vaccine prep, DCs crank out ATRA via ALDH1a2, halting their own growth, birthing weak macrophages, and recruiting regulator T cells that hush the fight. Tumors pump extra ATRA too, ignoring its cell-slowing effects while muting nearby T cells in the tumor zone.
The teams cracked this using mouse melanoma models, human cancer cell lines, and gene edits. They mapped ATRA receptors, confirmed enzyme must-haves with knockouts, and simulated vaccine conditions. Game-changer: computer modeling plus huge drug screens built KyA33—the first safe blocker of ALDH1a2/3 after 100 years of dead ends.
In mice, KyA33 revived DC maturity, supercharged vaccines to delay tumors, and solo shrank growths by unleashing T cells. It solved vitamin A’s paradox: lab tests show ATRA kills cancer cells, but high intake in people boosts cancer/death risk—tumors just tune it out, using excess to sabotage immunity instead.
Kang explains: "ATRA mutes key cancer defenses—we’ve got blockers proving preclinical power." New firm Kayothera targets trials for cancer, diabetes, heart issues. Funded by Ludwig, Komen, this unlocks immunotherapy 2.0.
REFERENCE:
1.Cao Fang, Mark Esposito, Ulrike Hars, Robert T. Byrne, Bokai Song, Jian Huang, Asael Roichman, Lawrence Shue, Xiaobing Cheng, John Proudfoot, Demin Zhao, Yong Wei, Ileana M. Cristea, Joshua D. Rabinowitz, Yibin Kang. Targeting autocrine retinoic acid signaling by ALDH1A2 inhibition enhances antitumor dendritic cell vaccine efficacy. Nature Immunology, 2026; DOI: 10.1038/s41590-025-02376-4
2.Mark Esposito, Cao Fang, Yong Wei, Alfonso Pozzan, Claudia Beato, Xiaoyang Su, Josiah E. Hutton, Tavis Reed, Xiang Hang, Enrico D. Perini, Wen Wang, Xiaobing Cheng, Yan Pan, Jianshi Yu, Maureen Kane, Malini Manoharan, John Proudfoot, Ileana M. Cristea, Yibin Kang. Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3. iScience, 2025; 28 (11): 113675 DOI: 10.1016/j.isci.2025.113675
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