RY103: A Novel IDO1 Inhibitor Targeting Immune Suppression and Angiogenesis in Glioblastoma Therapy

Glioblastoma is one of the most formidable challenges in modern cancer treatment. Known for its aggressive growth and resistance to standard therapies and even with the best available options—surgery, chemotherapy, and radiation—patients face a discouraging prognosis with poor survival rate of only about 15 months after diagnosis. This dismal outlook stems not only from the tumor’s ability to grow rapidly but also from its unique knack for evading the body’s immune defenses and adapting to treatment efforts. Another complicating factor is the tumor’s dense and complex network of blood vessels which ensures a steady supply of oxygen and nutrients that fuel its relentless progression. A major component in this process is vascular endothelial growth factor A (VEGFA) which glioblastoma cells overproduce to stimulate blood vessel growth (a process called angiogenesis). Anti-angiogenic therapies, designed to stop this blood vessel development have made some headway. Drugs like bevacizumab, for instance, target VEGFA in hopes of “starving” the tumor by cutting off its blood supply. However, these approaches often hit a roadblock, as glioblastoma tends to find alternative pathways for sustenance, sometimes becoming even more invasive when one route is blocked. Moreover, these treatments fail to address the tumor’s immunosuppressive tactics, which protect it from being recognized and attacked by the immune system. An important player in glioblastoma’s immune evasion strategy is the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which disrupts immune responses by depleting tryptophan in the tumor’s surrounding environment. This lack of tryptophan limits the activity of immune cells and encourages the growth of regulatory T cells (Tregs), which further suppress the body’s immune defenses. Given IDO1’s dual role in supporting the tumor’s growth and preventing immune response, finding suitable agents targeting against it presents an intriguing therapeutic approach and by this curb both the angiogenic (blood vessel-promoting) and immunosuppressive traits of glioblastoma in a single treatment.

This challenge is what inspired a new study led by Professor Qing Yang and conducted by a research team at Fudan University, and was recently published in the journal Pharmaceutics. Professor Yang’s team, including researchers Zikang Xing, Xuewen Li, Zhen Ning Tony He, Xin Fang, Heng Liang, Chunxiang Kuang, and Aiying Li, explored the potential of a novel IDO1 inhibitor known as RY103. The researchers assessed whether RY103 could effectively target both the angiogenic and immune-suppressing characteristics of glioblastoma. The researchers tested RY103 in the lab to see how effectively it could block IDO1 activity and tumor angiogenesis, focusing on glioblastoma that typically show high levels of this enzyme, after confirming the role and mechanism of IDO1 in blood vessel formation. The main question here was whether RY103 could reduce the breakdown of tryptophan and block tumor angiogenesis. Their findings were encouraging: RY103 significantly restricted IDO1 activity, helped keep tryptophan levels steady, which hinted at its potential to counter the immune-suppressing tactics of the tumor, lowered the expressions of angiogenic factors, and inhibited the tube-forming ability of angiogenesis model cells. This early success provided a strong basis for taking the research further, suggesting that RY103 could influence immune responses in the tumor’s environment. With promising lab results, the team moved forward to animal studies to observe RY103’s effects in more complex disease model. They first subcutaneously (i.e. “under skin”) implanted murine glioblastoma cells in model mice and confirmed that RY103 could also inhibit tumor growth and restrict blood vessel formation in tumors. They then implanted murine glioblastoma tumors in mice orthotopically (at the site where tumors originated), treating some of them with RY103 to see how it would affect tumor growth over time. The results stood out: mice treated with RY103 showed notably smaller tumors compared to those in the control group and those treated with 1-MT or INCB024360, other IDO1 inhibitors. Not only that, they also observed a significant drop in Tregs, which work to suppress the immune system around the tumor, shielding it from attack. Fewer Tregs in the tumor environment implied that immune cells now faced fewer barriers in targeting the tumor. By blocking IDO1, RY103 seemed to be ramping up the immune system’s natural response against the tumor, which pointed to its potential as a treatment that could boost the body’s defense. The researchers took it a step further by exploring how RY103 would work alongside another anti-angiogenic drug. They selected sunitinib, which is designed to stop tumors from growing new blood vessels. Another group of mice with subcutaneously implanted murine glioblastoma tumors received both RY103 and sunitinib to see if the combination would yield stronger anti-tumor effects. The results were promising: the combination therapy reduced tumor size even more than either drug on its own, and it also lowered the levels of angiogenic factors within the tumor. Their tumors also contained a larger number of Natural Killer (NK) cells—the immune system’s “attack cells” that target and destroy cancerous cells. The influx of NK cells in the tumor and spleens of mice suggested that RY103 was helping overcome some of glioblastoma’s powerful immune-evasion mechanisms, allowing the immune system to better recognize and attack the cancer cells. These findings suggested that RY103 and sunitinib worked well together—while sunitinib cut off the tumor’s blood supply, RY103 ramped up immune cell activity, striking at two of glioblastoma’s major survival strategies.

The researchers also needed to confirm that RY103 was safe to use, both alone and with sunitinib. The results were reassuring: neither RY103 on its own nor in combination with sunitinib showed any significant toxicity, highlighting RY103’s potential as a promising, safe treatment option.

What’s especially intriguing about the research work of Professor Qing Yang and her colleagues is its potential beyond just glioblastoma. The researchers’ combined approach—tackling immune suppression alongside angiogenesis—could apply to other types of cancer that also rely on these defenses to survive. In other words, RY103’s development is part of a broader movement in cancer treatment: finding ways to overcome the tactics that aggressive tumors use to adapt and thrive in the body. By showing that RY103 can work safely and effectively alongside sunitinib, an anti-angiogenic drug, the study hints that this kind of dual-action therapy could become a valuable tool in oncology, especially as the use of combination treatments gains ground in the fight against complex cancers. By combining immune activation with anti-angiogenic strategies, the team’s work here highlights how treatments can be fine-tuned to respond to the specific ways a tumor grows and evades the body’s defenses. Moreover, RY103’s ability to activate the immune system as well as block the angiogenic process while maintaining a favorable safety profile is particularly promising. This balance could make it a more patient-friendly option than traditional chemotherapy, which often comes with a range of harsh side effects. Altogether, this study doesn’t just advance the fight against glioblastoma; it builds a foundation for future treatments designed to address the most challenging aspects of cancer biology with a targeted, multi-layered approach.