Btnl9, or butyrophilin-like protein 9, is a member of the immunoglobulin families. It has been implicated in immune-related and cancer-related pathways [1]. In some cancers, its role seems to be associated with tumor-suppressive functions, potentially influencing tumor progression, immune cell infiltration, and prognosis.

In thyroid cancer (THCA), BTNL9 expression is down-regulated, and low expression is associated with a poorer progression-free interval. It shows stronger H3K27ac modifications in benign thyroid nodule tissues compared to papillary thyroid cancer tissues, indicating its possible role in tumorigenesis [1]. In breast cancer, BTNL9 expression is declined, and ectopic expression inhibits cell proliferation, colony formation, and metastasis, while knockdown has the opposite effect. It blocks breast cancer cells in the G2/M phase via the P53/CDC25C and P53/GADD45 pathways [2]. In non-small-cell lung cancer, lncRNA CALML3-AS1 inhibits BTNL9 transcription and expression, and BTNL9 down-regulation counteracts the antitumor effects of CALML3-AS1 depletion, suggesting its importance in NSCLC progression [3]. In uveal melanoma, high expression of BTNL9 is associated with a favorable prognosis, and it can suppress invasion but not proliferation [5]. In lung adenocarcinoma, BTNL9 expression is down-regulated and is associated with a poor probability of overall survival, and its expression is positively correlated with immune cell infiltration levels [6]. In pancreatic cancer, decreased expression of BTNL9 is associated with a reduced survival rate [7]. In BRAF-mutated peritoneal metastasis from colorectal cancer, increased expression of BTNL9 is observed, and drugs targeting BTN immune checkpoints could be a novel therapy approach [8]. In addition, a stop-gain variant in BTNL9 is associated with atherogenic lipid profiles in Polynesian populations [4], and there is a negative correlation between BTNL9 and the risk of amyotrophic lateral sclerosis [9]. In breast cancer, the expression of BTNL9 as one of the immune checkpoint genes was investigated, and its prognostic value was analyzed among different subtypes [10].

In conclusion, BTNL9 appears to play a crucial role in multiple biological processes, especially in cancer-related events such as tumor progression, metastasis, and prognosis. Its dysregulation is associated with various cancers, lipid-related disorders, and neurodegenerative diseases. The study of BTNL9 through different research models helps to understand its biological functions and provides potential biomarker and therapeutic target implications for these diseases.

References:

1. Zhang, Luyao, Yu, Shuang, Hong, Shubin, Li, Yanbing, Xiao, Haipeng. 2023. Comprehensive analysis of BTNL9 as a prognostic biomarker correlated with immune infiltrations in thyroid cancer. In BMC medical genomics, 16, 234. doi:10.1186/s12920-023-01676-8. https://pubmed.ncbi.nlm.nih.gov/37798795/

2. Mo, Qingfan, Xu, Ke, Luo, Chenghao, Wang, Long, Ren, Guosheng. 2021. BTNL9 is frequently downregulated and inhibits proliferation and metastasis via the P53/CDC25C and P53/GADD45 pathways in breast cancer. In Biochemical and biophysical research communications, 553, 17-24. doi:10.1016/j.bbrc.2021.03.022. https://pubmed.ncbi.nlm.nih.gov/33756341/

3. Zhang, Heng, Wang, Shao-Qiang, Zhu, Jie-Bo, Duan, Chao-Jun, Zhang, Chun-Fang. 2023. LncRNA CALML3-AS1 modulated by m6A modification induces BTNL9 methylation to drive non-small-cell lung cancer progression. In Cancer gene therapy, 30, 1649-1662. doi:10.1038/s41417-023-00670-7. https://pubmed.ncbi.nlm.nih.gov/37884580/

4. Carlson, Jenna C, Krishnan, Mohanraj, Rosenthal, Samantha L, Weeks, Daniel E, Minster, Ryan L. 2022. A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles. In HGG advances, 4, 100155. doi:10.1016/j.xhgg.2022.100155. https://pubmed.ncbi.nlm.nih.gov/36340932/

5. Jiang, Zhongming, Liu, Fei. 2019. Butyrophilin-Like 9 (BTNL9) Suppresses Invasion and Correlates with Favorable Prognosis of Uveal Melanoma. In Medical science monitor : international medical journal of experimental and clinical research, 25, 3190-3198. doi:10.12659/MSM.914074. https://pubmed.ncbi.nlm.nih.gov/31039142/

6. Ma, Weishuang, Liang, Jiaming, Mo, Junjian, Tian, Dongbo, Chen, Zisheng. 2021. Butyrophilin-like 9 expression is associated with outcome in lung adenocarcinoma. In BMC cancer, 21, 1096. doi:10.1186/s12885-021-08790-9. https://pubmed.ncbi.nlm.nih.gov/34635082/

7. Khojasteh-Leylakoohi, Fatemeh, Mohit, Reza, Khalili-Tanha, Nima, Batra, Jyotsna, Avan, Amir. 2023. Down regulation of Cathepsin W is associated with poor prognosis in pancreatic cancer. In Scientific reports, 13, 16678. doi:10.1038/s41598-023-42928-y. https://pubmed.ncbi.nlm.nih.gov/37794108/

8. Lund-Andersen, Christin, Torgunrud, Annette, Kanduri, Chakravarthi, Larsen, Stein G, Flatmark, Kjersti. 2024. Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer. In Journal of translational medicine, 22, 646. doi:10.1186/s12967-024-05467-2. https://pubmed.ncbi.nlm.nih.gov/38982444/

9. Lu, Chuan, Huang, Xiao-Xiao, Huang, Ming, Liu, Chaoning, Xu, Jianwen. 2025. Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses. In BMC neurology, 25, 82. doi:10.1186/s12883-025-04091-x. https://pubmed.ncbi.nlm.nih.gov/40033250/

10. Fang, Jun, Chen, Feng, Liu, Dong, Chen, Zhigang, Wang, Yuezhen. . Prognostic value of immune checkpoint molecules in breast cancer. In Bioscience reports, 40, . doi:10.1042/BSR20201054. https://pubmed.ncbi.nlm.nih.gov/32602545/