Have you ever imagined attacking a cancer cell from the inside out?

A team led by Peng Chen, professor of chemical biology at Peking University, reported in Nature a Trojan Horse-style intratumoural vaccine that sneaks into tumors and exposes them from within.

For decades, cancer treatment has relied mainly on surgery, chemotherapy and radiotherapy, which directly target tumors. More recently, immunotherapy emerged as a game-changer by mobilizing the body’s own immune defenses rather than attacking cancer cells outright.

However, immunotherapy does not work for everyone. Many cancers are known as "immune-cold tumors," meaning they are poorly recognized by immune cells. As a result, even an activated immune system may fail to detect and eliminate them. 

This is where the research team breaks new ground. Their vaccine doesn't just hunt the cancer – it forces it to reveal itself, turning hidden tumor cells into visible targets for the immune system.

Why some tumors evade immunity

T cells play a central role in immune defense. Their mission is simple: find abnormal cells, eliminate them and move on.

Cancer cells should be easy targets. Their mutations produce abnormal protein fragments, which act as molecular fingerprints signaling, "I don't belong here."

Some cancers, however, develop mechanisms to evade immune detection. One such strategy involves expressing PD-L1, a molecule that sends inhibitory signals to T cells and suppresses immune attack. When PD-L1 is present, T cells may fail to respond, allowing tumors to grow unchecked. 

This is a key reason why some patients, including those with cancers such as non-small cell lung cancer, do not benefit from existing immunotherapies.

Forcing cancer to expose itself

The research team has been working on targeted protein degradation technologies for several years. In 2021, the team developed GlueTAC, a technology that guides antibodies to bind tumor proteins and send them for cellular degradation.

But they did not stop there.

"Making antibodies bind more tightly or suppressing targets more strongly does not solve the real clinical problems," Chen emphasized. "Some patients still do not respond and tumors vary widely between individuals."

This conviction led to a bold new idea: what if cancer cells could be forced to degrade their own proteins and expose themselves to the immune system?

After four years of refinement, iVAC was developed, a chimeric intratumoural vaccine.

Rather than directly killing cancer cells or simply stimulating immune activity, iVAC is designed to make cancer cells process and expose their own antigens.

iVAC is a small molecule, weighing about 18 kDa, allowing it to penetrate solid tumors more effectively than many conventional drugs.

Despite its size, it carries out three coordinated missions. At its tip is a covalent nanobody that binds PD-L1, the tumor's "don't shoot" signal. Once attached, iVAC forces the cancer cell to swallow the entire complex, pulling PD-L1 into the cell's recycling center: the lysosome. Inside the lysosome, PD-L1 is degraded, dismantling the tumor's immune defenses. Simultaneously, antigen fragments are processed and displayed on the cell surface like unmistakable identity tags.

Harnessing immune memory

Even when tumors are exposed, another challenge remains: tumor-specific T cells may be limited in number or function.

But elsewhere in the body lies an untapped force: virus-specific memory T cells generated from past infections. They are abundant, highly trained and always on standby. These cells are the immune system's elite rapid-response force.

The researchers exploited this fact by equipping iVAC not with tumor antigens, but with viral antigens from common viruses like cytomegalovirus.

When iVAC decorates a cancer cell with viral markers, the immune system doesn't see a tumor; it sees a virus-infected cell.

And the immune system reacts instantly.

Memory T cells recognize what they believe is a viral threat and launch a full-scale attack, annihilating the cancer cells. This attack ignites immune memory, helping prevent relapse.

Experimental results speak volumes: across cell cultures, mouse models and patient-derived tumor systems, iVAC consistently outperformed conventional immunotherapies. Peer reviewers praised the work as "a highly encouraging discovery that lays a solid theoretical foundation for new therapeutic strategies."

From the lab to the clinic

iVAC is now moving toward clinical translation.

For patients with immune-cold tumors, it represents something rare in oncology: a second chance for immunotherapy to work.

Looking ahead, similar vaccines could be adapted to individual patients based on tumor type and immune history, advancing the goal of personalized cancer treatment.

While further studies are needed, the findings suggest that some tumors may no longer be able to remain hidden from the immune system.