近日，美国普林斯顿大学教授康毅滨及其研究组发现了通过抑制ALDH1A2靶向自分泌维甲酸信号传导增强抗肿瘤树突状细胞疫苗的效果。2026年1月5日出版的《自然—免疫学》杂志发表了这项成果。

该课题组人员发现GM-CSF–IL-4诱导的分化DC表达ALDH1A2并产生维甲酸，抑制DC成熟。基因敲除ALDH1A2释放这种自然刹车，增强DC功能。该课题组人员进一步开发了一种高效的ALDH1A2抑制剂，具有良好的药物样特性，没有脱靶效应的证据。用这种抑制剂治疗可促进DC活性，从而增强抗原特异性T细胞反应，提高DC疫苗的效力。他们的研究证明了ALDH1A2 -视黄酸轴在调节DC功能中的独特作用，并进一步提出了一种新的小分子ALDH1A2抑制剂作为潜在的癌症免疫治疗剂。

研究人员表示，刺激树突状细胞（DC）活性的策略，如体外生成和启动DC疫苗，已经被探索作为癌症免疫疗法，因为它们有可能引发抗肿瘤T细胞反应。尽管经过了几十年的研究，但DC疫苗的成功仍然有限，可能是由于未知的耐受性强制机制。

附：英文原文

Title: Targeting autocrine retinoic acid signaling by ALDH1A2 inhibition enhances antitumor dendritic cell vaccine efficacy

Author: Fang, Cao, Esposito, Mark, Hars, Ulrike, Byrne, Robert T., Song, Bokai, Huang, Jian, Roichman, Asael, Shue, Lawrence, Cheng, Xiaobing, Proudfoot, John, Zhao, Demin, Wei, Yong, Cristea, Ileana M., Rabinowitz, Joshua D., Kang, Yibin

Issue&Volume: 2026-01-05

Abstract: Strategies to stimulate dendritic cell (DC) activity, such as ex vivo generation and priming of DC vaccines, have been explored as cancer immunotherapies owing to their potential to elicit antitumor T cell responses. Despite decades of research, the success of DC vaccines has been limited, potentially because of unidentified tolerance-enforcing mechanisms. Here we show that GM-CSF–IL-4-induced differentiating DCs express ALDH1A2 and produce retinoic acid, inhibiting DC maturation. Genetic knockout of Aldh1a2 releases this natural brake and enhances DC function. We further develop an ALDH1A2 inhibitor with high potency, favorable drug-like properties and no evidence of off-target effects. Treatment with this inhibitor promotes DC activity, which in turn enhances antigen-specific T cell responses, improving the efficacy of DC vaccines. Our study demonstrates the unique role of the ALDH1A2–retinoic acid axis in regulating DC functions and further presents a new small-molecule inhibitor of ALDH1A2 as a potential immunotherapeutic agent for cancer.

DOI: 10.1038/s41590-025-02376-4

Source: https://www.nature.com/articles/s41590-025-02376-4