Cancer research rarely advances in straight lines. Progress often begins with questions that feel uncertain, sometimes even uncomfortable. Not questions aimed directly at the clinic, but questions driven by curiosity: why does this happen at all? For Oncode Investigator Reuven Agami (Netherlands Cancer Institute), that uncertainty has always been a source of energy.

That curiosity has now grown into something far larger than a single lab or country can carry. On Wednesday 4 March 2026, Cancer Grand Challenges announced five new global research teams selected to take on some of the toughest, most persistent problems in cancer research. Chosen from hundreds of international proposals, these teams represent a total investment of up to $125 million in bold, high-risk science: work no single institution could tackle alone.

One of the selected teams is ILLUMINE, led by Agami. The team also includes Oncode Investigators Sebastiaan van Heesch (Princess Máxima Center) as a co-Investigator and Ton Schumacher (Netherlands Cancer Institute) as a collaborator. Van Heesch will provide his expertise in studying extremely small proteins, and Schumacher is central in developing new cancer immunotherapy tools.

Together, the ILLUMINE mission is to explore one of the most elusive frontiers in cancer biology: the dark proteome—a hidden layer of proteins produced by cancer cells that largely escapes today’s genomic tools. What follows is not just the story of a major international award, but the journey behind one of the selected teams: from curiosity-driven observations to a global effort to shed light on what cancer hides.

The call that changed everything

Agami remembers the moment vividly. Not the only call itself, but the email that came before it. “They don’t call you first,” he says. “They email you that they are going to call you.” The message arrived late morning: in two hours, there would be a phone call. No explanation.

“It is nerve-breaking,” he says. “If it’s only about me, fine. But this is about a huge group of people, a lot of commitment, a lot of responsibility. You really feel it.”

By the time the call came, colleagues were already checking in. Everyone was waiting. When the decision was confirmed, relief mixed with something heavier: the realisation that this was no longer just an idea: it is now a shared responsibility.

From observation to Cancer Grand Challenges

For Agami, the ILLUMINE story did not begin with a grant application. It began years earlier, almost accidentally. Since around 2016, Agami’s lab has been studying how cancer cells behave under stress, when nutrients run low, or when the immune system attacks, as it does during immunotherapy.

Healthy cells respond by slowing down. They conserve energy and pause protein production. Cancer cells ignore and continue. “As long as they can produce something, they keep going,” Agami explains. “But the quality of what they produce drops quite profoundly.”

The surprise was that when we looked for protein errors, we not only found them, but they were not random. Cancer cells produce abnormal proteins: unintended protein fragments, specific mutants, and a group of extremely small peptides. None of these products can be directly predicted from DNA or RNA alone. For years, they remained invisible, simply because researchers were not looking for them.

This hidden biology is what Agami and van Heesch call the dark proteome. “For decades, we have been studying the tip of the iceberg of our proteins,” he says. “But a large part of what cells actually produce has been below the detectable surface.” Only recently have new technologies made it possible to start uncovering that submerged world, and cancer – we suspect - appears to exploit it extensively.

Why the dark proteome matters

The implications are profound. Many dark proteins appear only in cancer cells, not in healthy tissue. Some are displayed on the surface of tumour cells, where they can be recognised by the immune system. Others are released into the tumour microenvironment, potentially influencing immune cells and surrounding tissue.

ILLUMINE aims to systematically map and understand this dark proteome across several hard-to-treat cancers, including pancreatic, pediatric brain cancer, ovarian, and lung cancer. The strategy is deliberately twofold. On one hand, the team will explore whether these cancer-specific proteins can serve as new targets for immunotherapy - allowing the immune system to recognise what it has never seen before. On the other hand, they will investigate the fundamental mechanisms behind their production, laying the groundwork for future treatment strategies that do not yet exist.

“It’s not enough to say: let’s do clinical trials,” Agami says. “You need to identify new mechanisms that can lead to new treatment possibilities. You do not know if they will deliver, but it is the only way I know to make major breakthroughs.”

A truly global effort

The ambition of ILLUMINE is precisely why it requires a global team. Researchers from Europe, the United States, and Israel bring together expertise in proteomics, immunology, clinical oncology, and data science. Samples, analyses, and data move across borders, requiring shared infrastructure and careful coordination.

Leading such a consortium marks a new chapter in his career. He now coordinates a complex international collaboration, supported by shared infrastructure and close coordination at the Netherlands Cancer Institute. His work is also embedded within the Oncode Institute, which supports curiosity-driven research while keeping patient impact in sight.

“For 25 years, I ran my own research line,” Agami says. “Now I am coordinating something much bigger.” Luckily, the Netherlands Cancer Institute provides the organisational backbone, with dedicated management and support to ensure the collaboration will function smoothly. The team plans a joint kick-off meeting in Amsterdam this summer, the first time all collaborators will gather in one place to discuss science.

Staying close to patients

Despite the scale, Agami keeps returning to something personal. Every day, he bikes into the institute, parks below the hospital, and walks through the corridors. “You see the patients,” he says. “And you think: maybe one day, something we build here will help.”

He is careful not to promise quick cures. The path from discovery to patient impact is long and often slow. But he believes the direction matters. By shining light on what cancer hides, rather than only exploiting the known, ILLUMINE opens a fundamentally new way of thinking about the disease.

“If, in five or ten years, this work changes how we understand cancer,” Agami says, “and gives others new ways to fight it, then it has done what it needed to do.”