Inhibiting Vitamin A Metabolism Pathway Enhances Cancer Immunotherapy in Preclinical Models

A metabolic byproduct of vitamin A has been identified as a hidden saboteur of cancer immunotherapy, with researchers now blocking its action to revive immune defenses.

The study, led by the Princeton University Branch of the Ludwig Institute for Cancer Research, reveals that all-trans retinoic acid (ATRA) suppresses anti-cancer immune responses by reprogramming dendritic cells (DCs) to promote immune tolerance.

ATRA is produced by both DCs and cancer cells through enzymes ALDH1a2 and ALDH1a3. This metabolic pathway undermines the efficacy of dendritic cell vaccines, a critical strategy in immunotherapy. The researchers developed KyA33, a drug designed through computational modeling and high-throughput screening, to inhibit these enzymes and block ATRA production.

In preclinical models, KyA33 restored DC function, enhanced vaccine efficacy, and delayed tumor growth in melanoma models. Notably, the compound also demonstrated independent immunotherapeutic activity.

The study clarifies a paradox: while retinoids like ATRA show anti-cancer effects in lab experiments, high vitamin A intake correlates with increased cancer risk in populations. The authors attribute this discrepancy to ATRA’s immune-suppressive role rather than direct antiproliferative effects.

This distinction highlights the pathway’s potential for therapeutic intervention.

A new biotechnology company, Kayothera, has been established to advance ALDH1A inhibitors into clinical trials for cancer, diabetes, and cardiovascular disease.

The research was supported by the Ludwig Institute for Cancer Research, the National Science Foundation, the American Cancer Society, and private foundations. The team emphasizes the need for further validation in human trials to assess safety and efficacy.