Int J Biol Sci 2022; 18(1):166-179. doi:10.7150/ijbs.64094 This issue

Research Paper

Conjugate of ibrutinib with a TLR7 agonist suppresses melanoma progression and enhances antitumor immunity

Sumei Ren1,2, Xiaodong Wang1✉, Guangyi Jin1✉

1. School of Pharmaceutical Sciences, Nation-Regional Engineering Lab for Synthetic Biology of Medicine, International Cancer Center, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, China.
2. Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Ren S, Wang X, Jin G. Conjugate of ibrutinib with a TLR7 agonist suppresses melanoma progression and enhances antitumor immunity. Int J Biol Sci 2022; 18(1):166-179. doi:10.7150/ijbs.64094. Available from

File import instruction


Graphic abstract

The use of large molecules for immunotherapy has led to exciting developments in cancer treatment, such as the development of PD-1/PD-L1 antibodies. However, small molecule targeted therapies still lack effective immune-functional classes. Ideal anticancer drugs should simultaneously generate immune memory when killing cancer cells to prevent tumor relapse and metastasis. To this end, we carried out a rationally designed strategy to develop novel classes of small molecule compounds with bifunctional targeting and immunostimulatory abilities by conjugating targeting compounds with TLR7 agonists, generating immune-targeting conjugates (ImmunTacs). GY161, as a representative ImmunTac, was synthesized via chemical conjugation of ibrutinib with a TLR7 agonist. In vitro, GY161 stimulated the production of cytokines by mouse spleen lymphocytes, promoted the maturation of dendritic cells (DCs), and inhibited the growth and induced the apoptosis of B16 melanoma cells by regulating the c-Met/β-catenin pathway. In vivo, GY161 enhanced the frequency of CD8+ T cells in spleens and tumors, suppressed the growth of B16 melanoma cell-derived tumors and prolonged the survival time of mice. In summary, GY161 could prevent melanoma progression through direct tumor killing and by triggering specific immunity. These results strongly suggest that ImmunTacs are a reliable and promising strategy for developing small molecule immunogenic anticancer drugs.

Keywords: ibrutinib, TLR7 agonist, melanoma, immunotherapy