Charlie Swanton: Preventing cancer, and the two-step model

What is the future of cancer medicine...
28 January 2025

Interview with 

Charlie Swanton, Francis Crick Institute

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If the immune system is capable of fighting cancer, why does it need to be coaxed into it. Why not do it by itself?

Charlie – I think it does, but the tumour finds ways to subvert it. One of the key ways the immune system fails to recognise a tumour cell is because the tumour cell downregulates the expression of surface proteins called HLA (human leukocyte antigen), also known as MHC. These proteins essentially allow the body to distinguish between self and non-self.

Due to the processes I mentioned earlier—genetic diversity and selection—you’ve got a sort of predator-prey relationship, where the predator is the immune system and the prey is the tumour cell. The tumour evolves to adapt and evade the immune system by subverting those surface molecules that enable the immune system to differentiate self from non-self. This is one of the mechanisms by which tumours can evade predation by immune T-cells.

Chris – So the solution is simply to switch off that brake on the immune system, and that ought to deal with all cancers? Or do you think some cancers will respond while others remain almost impossible to crack?

Charlie – That’s a great question. The number of tumour types responding to these drugs continues to grow. Even tumour types I would have assumed wouldn’t respond to these treatments—particularly in early disease—are showing sensitivity. For example, recent data shows that patients with oestrogen receptor-positive breast cancer respond to immune checkpoint blockade, even though these tumours typically have relatively few mutations.

This raises important questions about what the immune system is actually recognising in these tumour cells. While mutations are part of what the immune system identifies, there are clearly other factors at play that we don’t fully understand yet.

Chris – As our confidence in gene editing increases, are we moving towards a point where we could think, “We know what’s gone wrong with the cancer cell; we know where those cells are, and we can target them selectively”? Could we use gene editing in situ to address the cancer and any metastatic deposits, or is that too risky?

Charlie – By the time a patient presents with cancer, particularly late-stage cancer, the disease burden can be enormous—hundreds of millions or even billions of cells. The challenge here is delivery: how do you deliver gene-editing technology to such a vast number of cells? It only takes a few cells to escape for resistance to emerge. You would need to target every single cell, and that’s a significant challenge.

Chris – But isn’t that where the immune system comes in? Could we adopt a multi-pronged approach—using gene editing, immune checkpoint inhibitors, and the immune system itself—to attack the cancer on multiple fronts?

Charlie – Yes, that’s potentially the right strategy. But this is still early days. Gene editing is in its infancy, and while it’s hugely exciting, delivery remains one of the biggest obstacles for gene therapy and gene editing technologies. This has been a challenge since my training days, and it continues to be.

Chris – Are we perhaps going about this the wrong way? It feels like we’re trying to close the stable door after the horse has bolted. Shouldn’t we be putting more energy into diagnosing people much earlier and stopping cancer at a stage where it hasn’t yet become billions of cells? Once it’s reached that stage, it’s very hard to turn back.

Charlie – That’s exactly the conclusion many of us have reached. Our work in TracerX, along with research from many other investigators worldwide, has shown that tumours have so many evolutionary paths for growth and adaptation that achieving cures in late-stage disease is extraordinarily difficult. I never say never, but it makes you think: how can we maximise the good we do for the greatest number of patients within a 20-year career?

Right now, we’re focusing on early diagnosis, as you mentioned, but also going one step further—towards prevention. How can we attenuate tissue inflammatory pathways to stop cancer from developing in the first place? Which inflammatory pathways can we block to reduce cancer risk while still enabling the immune system to fight infections? These pathways exist for a reason—they protect us from microbes, viruses, and bacteria. So we need to find subtle ways to prevent cancer without compromising our ability to combat infections.

Chris – During this interview, you’ve mentioned several cases where you’ve completely revised your understanding of how this disease works. If I could wave a magic wand and give you the answer to one big question, what would it be? What would you like to solve before the end of your career?

Charlie – There is one question I’d really love to answer. I mentioned earlier the work of Isaac Berenblum and Alan Balmain on the two-step model of cancer initiation: you need mutations and an inflammatory mediator. The big question is, how do those two collaborate?

What is the inflammatory mediator doing to the stem cell where that cancer-causing mutation resides? I suspect there’s a switch—a mechanism that activates cancer development. If we could identify that switch and find ways to turn it off, we could potentially target the very first step of cancer initiation, even in late-stage disease.

Chris – And when you leave the Crick in the evening, what do you do to switch off?

Charlie – I don’t switch off. I keep thinking about these problems.

Chris – There’s a bottle of Shiraz on your desk. Does that help?

Charlie – I probably shouldn’t admit this, but yes.

Chris – A Christmas present, by the looks of it?

Charlie – Yes, it helps. But even when relaxing, your mind wanders back to these questions. You wake up at 2 a.m. and think, “Eureka, that’s the solution!” Those moments happen less often than they used to 20 years ago, but this job is so exciting. It’s hard not to think about it, even when you’re unwinding.

We spend a lot of time talking to other scientists socially because that’s what we love. This job has real purpose and tangible impact—it’s a privilege to be part of it.

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