Scientists Map, Cell by Cell, How Liver Cancer Hides and Spreads to the Lungs

Researchers have built a detailed, stage-by-stage map of how liver cancer cells travel to the lungs and evade the immune system — and identified a fleeting cellular state that may be a weak point for stopping cancer from spreading.

The team, led by Yunfan Sun at Zhongshan Hospital, Fudan University, combined high-resolution spatial transcriptomics, single-cell RNA sequencing and chromatin-accessibility profiling to watch metastasis unfold across nine sequential stages, in mouse models of hepatocellular carcinoma and in human metastatic samples. Published July 30, 2026 in Science.

Why metastasis has been hard to study

The process is what kills most cancer patients, and it has been substantially less well characterised than primary tumour growth for a practical reason.

Metastasis is rare at the cellular level. Enormous numbers of cells leave a primary tumour and almost all die — in circulation, on arrival, or shortly after. The few that succeed are a tiny minority, and they are dispersed, transient and difficult to find.

Established metastases can be studied because they are large. The stages before that — a handful of cells arriving in a new organ and surviving there — have been largely invisible.

Combining spatial and single-cell methods across nine defined stages is what makes those intermediate states observable.

The dormant state

Early on, rare wandering tumour cells slip into a quiet, dormant-like state, marked by high activity of a gene called Phgdh.

Dormancy is a recognised clinical phenomenon with a long-standing mechanistic gap. Patients treated successfully for cancer can relapse years or decades later, which implies cells survived somewhere in a non-dividing state, invisible to detection and unaffected by treatments that target dividing cells.

Phgdh encodes an enzyme in serine biosynthesis, and its involvement suggests the dormant state is metabolically distinctive — which would make it potentially targetable, since metabolic dependencies can be blocked pharmacologically.

Going dark

In that state, the cells switch off distress-signal molecules that would normally summon immune cells — effectively going dark to evade detection.

This is a distinct evasion strategy from the ones most therapies address. Checkpoint inhibitors work against tumours that immune cells have found but cannot attack, releasing brakes the tumour applies.

A cell that is never detected presents a different problem. There is no brake to release, because no immune response was mounted — which would explain why immunotherapy does little to prevent metastasis even when it controls established disease.

The supporting cast

Supporting lung cells and a specific type of macrophage then help the hidden cancer cells settle and expand into full metastases.

That fits an established concept: metastasis requires a receptive site, not merely a cell that arrives. Tissue is not passive, and cells that reach an unprepared environment generally die there.

Macrophages are recurrent participants in this. They are tissue-resident immune cells with broad functions including tissue repair and remodelling, and tumours frequently co-opt those repair functions — obtaining growth factors, matrix remodelling and suppression of other immune cells from a cell whose ordinary job is healing.

Reversing the hiding

When the researchers disrupted the hiding mechanism — genetically or with drugs — the immune system regained the ability to spot the cancer, and metastatic growth shrank.

The pharmacological result is what elevates this above description. A genetic experiment shows a gene is necessary; a drug producing the same effect shows the state can be disrupted from outside, which is what a therapy would need to do.

The narrow window

Because the vulnerable states are transient, the authors suggest they open narrow therapeutic windows to intercept cancer spread before established tumours form.

That is the finding’s promise and its central difficulty. Intervening during a transient early state means treating patients who have no detectable metastases — so the treated population cannot be identified by imaging, and benefit can only be demonstrated by preventing relapse over years.

Why liver cancer spreads to lungs specifically

Metastatic patterns are not random, and the liver-to-lung route the study follows is among the most predictable in oncology.

Part of the explanation is plumbing. Blood leaving the liver returns through the hepatic veins to the heart and then directly to the lungs, so the pulmonary capillary bed is the first fine filter that a circulating liver tumour cell encounters. Cells too large to pass lodge there.

Mechanical trapping alone does not account for it, though. Many cancers shed cells that lodge in lung capillaries without producing metastases, and organ preference varies between tumour types in ways circulation cannot explain — prostate cancer to bone, colorectal to liver.

The longstanding framework holds that a disseminating cell must find a compatible environment: the right growth factors, matrix composition and cellular support. Arrival is necessary and not sufficient.

Finding that lung cells and specific macrophages actively assist arriving liver cancer cells gives that framework mechanism. It suggests organ preference is partly about which tissues can be persuaded to cooperate — and that interfering with the host side may be as viable a target as the tumour cell itself.

The findings are early and mechanistic, but they point toward new strategies aimed at metastasis, the process responsible for most cancer deaths. Research news, not medical advice.