Genetic mutations cause cancer. This idea has long driven strategies that aim to lower risk or determine when to look for early signs of disease. Don’t smoke. Minimize alcohol. Get vaccinated against viruses linked to cervical or liver cancer. Lifestyle changes can reduce the chances our cells accumulate DNA mutations that make them grow out of control.
But we might be missing part of the picture. Some people with cancer-related mutations never develop the disease. Others live healthy, have no family history, and suddenly learn they have cancer—and it’s already spread.
To Miriam Merad at Mount Sinai in New York, inflammation is the other half of the puzzle. Cells that acquire mutations and begin to take on cancer-like traits sometimes remain benign, likely because the immune system keeps them in check. By amping up the body’s own surveillance in people with abnormal growths—before they turn malignant—it might be possible to stop tumors from developing in the first place.
The new field, called cancer interception, is gaining steam. Clinical trials for lung cancer are in the works. Cancer vaccines, which train the immune system to destroy abnormal cells, have shown early promise. In one trial, roughly 90 percent of participants with pancreatic abnormalities generated immune cells better able to recognize mutated cells.
Other researchers are taking the idea further. In one study, they gave mice with precancerous pancreatic growths an approved drug to ward off the growths’ transformation into cancer, reshaping the immune landscape and extending survival.
“Yes, those mutations absolutely contribute to dysregulation of the cell that will become cancerous,” said Merad in an interview with Nature. But that’s not enough. The realization that inflammation is somehow “necessary for cancer initiation suggests that we can intervene.”
The Life of a Cancer
Cells don’t turn cancerous overnight. This is what makes the disease so insidious. With aging, environmental hazards, or simply replication, cells constantly pick up DNA changes. Most mutations are relatively harmless.
Occasionally, however, a mutation hits a driver gene that gives a cell an advantage over its neighbors. A gene called KRAS, for example, normally encourages growth. But mutated versions become stuck in the “on” position, continuously ordering cells to divide. Another gene, P53, often dubbed the “protector of the genome,” can lose its ability to eliminate damaged cells. And when DNA-repair genes go awry, mutations can accumulate even faster.
A driver mutation doesn’t necessarily make a cell cancerous. Evolutionarily, it gives the cell a leg up. Armed with the ability to divide and resist death, its descendants gradually take over the cellular neighborhood, competing with healthy cells for space, nutrients, and survival signals. Rapid expansion also means the cells pick up more mutations in a dangerous feedback cycle.
Eventually, some gain the genetic and molecular signatures of a precancerous cell. Most of these remain harmless for decades. Others rewire their surroundings, setting up a hostile environment that blocks immune cell surveillance and boosts inflammation, eventually allowing them to spread uncontrollably.
Researchers aim to halt that journey with cancer interception.
Going on Offense
For years, scientists have believed cancer causes local immune system changes. When they reach a tumor, some immune cells go rogue. Macrophages, rather than literally eating up the enemy, are reprogrammed by the tumor microenvironment to dampen other immune cells.
This process may start earlier than expected. Last year, Merad and colleagues found that tumors send cues to bone marrow precursor cells, nudging them towards a pro-cancer macrophage state. By the time they reach tumors, the protectors have already turned to the dark side.
“This work changes the way we think about the timing of immune suppression in cancer,” said study author Samarth Hegde in a press release. “We need strategies to intervene much earlier, while these cells are still developing, so we can stop them from becoming cancer’s allies in the first place.”
The team found one protein, NRF2, acted as a switch. Inflammation from the tumor environment changed the protein’s function, such that it encouraged nascent macrophages to become immune-suppressive. Blocking NRF2, either by disabling its gene or with drugs, led to a stronger immune attack against early lung cancer in mice.
The results inspired a new way to fight cancer. In addition to attacking a tumor, treatments should also work to change the environment that helps it grow.
Hegde and collaborators are now testing the idea with an existing drug from Novartis. Originally developed for heart and blood vessel disease, the drug, canakinumab, surprisingly slashed lung cancer incidence and death by over 67 percent in an earlier trial cohort of roughly 10,000. The unexpected findings inspired researchers to study inflammation as a driver of cancer.
In mice genetically engineered to develop lung cancer, blocking the same inflammatory pathway similarly reduced eventual tumors and shifted the lungs’ immune environment towards a stronger attack on budding tumors. And a new study found other potential targets for interception in immune cell networks as precancerous lung cells developed.
Merad’s team, alongside collaborators, are launching the Can-Prevent-Lung trial to test canakinumab in people with persistent, high-risk lung growths. CT scans can spot these abnormalities, but not all will become cancers. Figuring out who actually needs the treatment is an open question.
Medications have side effects, and “we never give a drug to someone that doesn’t need it,” said Merad.
Other teams are grappling with a similar dilemma. One solution may be catching cancer earlier. The PRECEDE trial aims to monitor over 20,000 people with a family history of pancreatic cancer or abnormal growths to see if frequent checkups improve survival. Like lung cancer, pancreatic cancer is notoriously dangerous. The diseased cells are often highly invasive, avoid most treatments, and cause vague symptoms that make diagnosis difficult.
The team plans to explore whether a blockbuster pancreatic drug, daraxonrasib, currently approved only for advanced cancer, can boost survival when given after pre-cancer growths are removed. They’ll also test whether AI can spot tiny abnormalities invisible to the naked eye in medical scans, flagging people who might benefit from interception.
Although experts are excited about the tactic, a thorny question remains: Will people take powerful drugs when they don’t actually have cancer? Daraxonrasib, for example, can cause rashes so severe that some patients stopped taking it, along with other side effects.
The best candidates may be identified by a marker often missed during checkups. We never monitor inflammation levels, said Merad. Her team is now evaluating a blood test and developing cheaper, easier strategies for cancer screening. Better risk prediction might help doctors decide whether to intercept cancer or leave benign growths alone, opening the treatment philosophy to more people.
It won’t be easy, but to Merad, the future is bright. “It’s an extraordinary time of optimism and possibilities,” she said. From biotechnology advancements to AI that can integrate biochemical and imaging datasets, “it is impossible not to be hopeful.”
