UM research reveals new mechanism underlying synergistic effects between anticancer drugs and immunotherapy

A research team led by Chuxia Deng, chair professor in the Faculty of Health Sciences (FHS) at the University of Macau (UM), has discovered that CDK4/6 inhibitors (CDK4/6i) regulate tumour-associated macrophage (TAM) subtypes to indirectly activate CD8+ T cell–mediated anti-tumour immunity, thereby significantly enhancing tumour responses to low-dose PD-1 immune checkpoint inhibitors (ICB). This finding reveals a new immunoregulatory mechanism governing the tumour cell–macrophage–CD8+ T cell interaction loop and offers new insights for precision immunotherapy. The study has been published in the leading international journal Advanced Science.

In recent years, CDK4/6 inhibitors have been widely used as cell cycle-regulating drugs for solid tumours such as breast cancer. These agents not only directly induce tumour cell growth arrest but also markedly improve the immune status of the tumour microenvironment (TME). The study confirms this effect across multiple experimental platforms, including animal models, tumour tissue slice cultures, and human tumour samples. Specifically, CDK4/6i prompts tumour cells to secrete large quantities of macrophage migration inhibitory factor (MIF), thereby driving tumour-associated macrophages toward an M1 phenotype that supports immunity. These M1 macrophages further activate intratumoural CD8+ T cells, enhancing cytotoxicity and anti-tumour efficacy, and thereby strengthening responses to PD-1 ICB therapy.

The UM research team also found that conditioned medium from M1 macrophages trained by CDK4/6i, when combined with low-dose PD-1 antibody, can synergistically enhance tumour immune responses. This discovery provides a theoretical basis for overcoming low response rates in solid tumours and for optimising immunotherapy strategies. The study also uses cutting-edge techniques, including single-cell transcriptomics and spatial immunofluorescence imaging, to comprehensively elucidate the mechanisms and networks by which CDK4/6i regulates the immune microenvironment.

Chuxia Deng is the corresponding author of the study, with He Lin, a doctoral student in FHS, as the first author. FHS Associate Professors Zhao Qi and Liu Tzu-Ming; postdoctoral fellows Lei Haipeng and Feng Yangyang; doctoral students Peng Yuzhong, Tang Dongyang, Zhu Xiangpeng, Mou Di, and Qiao Yunfeng; as well as the Biological Imaging and Stem Cell Core and the Animal Research Core at UM also contributed to the study. Collaborative partners included the team led by Tam Kwong Hang, chair professor at the Macau University of Science and Technology (MUST), and the MUST Hospital. The research was supported by the Science and Technology Development Fund of the Macao SAR (File Nos: 0009/2022/AKP, 0129/2024/RIA2). The full version of the research article is available at: https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/advs.202511330.

To read the news on UM’s official website, please visit the following link:
https://www.um.edu.mo/news-and-press-releases/campus-news/detail/63169/