Turning cancer’s protein machinery against itself to boost immunity

Researchers from the University of Liège and international collaborators have discovered an unexpected way to to stimulate the immune system against cancer: by subtly disrupting how tumour cells manufacture their proteins.

The study, recently accepted for publication in Nature Communications, reveals that cancer cells rely on a highly precise protein-production system to remain to evade immune attack. When this system is perturbed, tumours can suddenly become vulnerable to immune recognition and elimination by the body’s own defenses.

When protein quality control becomes cancer’s shield

All cells constantly produce proteins based on genetic instructions. To do this accurately, they rely on molecular “adaptors” called transfer RNAs (tRNAs), which ensure proteins are built correctly. Cancer cells exploit this system to maintain stability and avoid triggering immune responses.

The research team discovered that a specific tRNA modification, controlled by an enzyme called KEOPS, plays a crucial role in helping melanoma tumours evade immune detection. When this modification is disrupted, cancer cells begin producing misfolded proteins that accumulate inside the cell.

“By disrupting this quality‑control mechanism, we force the tumor to reveal what it normally works hard to hide,” explains Pierre Close, Director of the Laboratory of Cancer Signaling. “This buildup of faulty proteins acts as a warning signal: it triggers an immune response similar to the one activated during viral infections. It’s an entirely new way of activating antitumor immunity.”

Rather than being harmless, this buildup acts as a distress signal: it activates an innate immune sensor normally used to detect viral infections. This, in turn, attracts and activates immune T cells, which infiltrate the tumour and drive its rejection.

In preclinical models, blocking this pathway transformed “cold” tumours, typically unresponsive to immune attack, into “hot” tumours that became infiltrated by immune cells and showed markedly reduced growth.

A new strategy to make resistant tumours treatable

Immunotherapies have revolutionized cancer treatment, but many tumours remain resistant because they evade effective immune attack. This study highlights a fundamentally new approach: instead of directly stimulating immune cells, researchers can render tumour cells more susceptible to antitumor immunity by altering how they produce proteins..

“Our work shows that the stability of protein production can become a true Achilles’ heel for tumors,” says Cléa Dziagwa, Télévie PhD candidate and first author of the publication. “Understanding how tRNAs influence immune evasion opens the possibility of intervening where conventional immunotherapies fail.”

 

By linking RNA biology, protein quality control and anti-tumour immunity, the work opens new avenues for therapeutic development. Targeting tRNA modifications could represent a strategy to enhance current immunotherapies or to treat cancers that currently do not respond.

From fundamental discovery to translational ambition

This work was carried out at the GIGA Institute of the University of Liège, in collaboration with international partners in the UK and Germany, and supported by FNRS and WELRI/WELBIO. It reflects the growing strength of Belgian research in RNA biology and cancer immunology.

For clinician-scientists involved in the project, the findings also shape future ambitions: translating discoveries on RNA and protein synthesis into new therapeutic strategies for difficult-to-treat cancers. By understanding how tumours control their internal protein machinery to escape immune detection, researchers hope to design interventions that re-engage the immune system and improve patient outcomes.

Ultimately, this study underscores a central idea: sometimes, making cancer vulnerable is not about attacking it directly, but about revealing it to the immune system.

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