International Business Department           Liu Bojia           May 9, 2025

  Cancer is one of the major challenges in medicine today. Among various types of cancer, pancreatic cancer is known as the ‘king of cancers’ due to its rapid progression and high mortality rate. Relevant statistics show that the five-year survival rate of pancreatic cancer patients is less than 10 per cent. Not only is the effect of traditional chemotherapy and radiotherapy limited, but the performance of immunotherapy in pancreatic cancer is also far less significant than in other cancers.

  The reason why pancreatic cancer is so difficult to treat is closely related to its complexity and insidious nature. The tumour tissue of pancreatic cancer contains a large number of stromal cells and constitutes a complex tumour microenvironment with various types of immune cells. The actual harmful cancer cells tend to be underrepresented and hidden deep within the tumour, which makes it more difficult for immunotherapy to work; in addition, pancreatic cancer tumours tend to have a low mutational load, which means that they don't have enough antigens to be recognised by immune cells. Therefore, finding new antigenic targets has become the key to breaking the bottleneck of immunotherapy for pancreatic cancer.

  In the latest issue of Science, a team of researchers from the Massachusetts Institute of Technology, Dana-Farber Cancer Institute have systematically explored for the first time a special class of antigens, cryptic peptides, in pancreatic cancer cells. These antigens are not derived from conventional protein-coding genes, but from ‘non-coding’ regions of the genome. Although not involved in protein production, they can in some cases produce peptides through aberrant translation. The new study identified about 500 cryptic antigenic peptides that are found only in pancreatic cancer tumours, and by generating T-cells that target the antigenic peptides, the researchers succeeded in directing the T-cells to efficiently clear the pancreatic cancer cells. This may bring a new opportunity to treat the ‘king of cancers’.

  In the study, the authors first obtained tumour tissue samples from pancreatic cancer patients and constructed a number of tumour organoids based on them. These organoids were able to replicate and mimic pancreatic tumour structure and development. The results showed that as the organoids grew, a large number of nascent antigens were generated in the tissues, but most of them were cryptic antigenic peptides. About 1,700 cryptic antigenic peptides were identified from the study, with an average of 250 per tumour organoid.

  Subsequent analysis found that about 500 cryptic antigenic peptides were present only in pancreatic cancer cells and not in healthy tissues, and the researchers further classified these peptides as cancer-restricted cryptic antigenic peptides. They then selected more than 30 of these antigenic peptides to be exposed to the T-cell environment. As a result, 12 antigenic peptides significantly stimulated T cells to produce specific immune responses. These activated T cells were able to recognise and kill pancreatic cancer cells expressing the corresponding antigenic peptides, with no effect on normal cells.

  With the above findings, the researchers found a potential new direction to enhance T cells. With the help of CRISPR/Cas9 technology, they introduced the T-cell receptor that recognises these cancer-restricted cryptic antigenic peptides into natural T-cells and constructed a batch of TCR-T cells.

  In the experiments, these TCR-T cells showed strong tumour killing ability. They not only quickly identified target pancreatic cancer cells, but also released perforin and granzyme to directly kill cancer cells, or secreted interferon γ and tumour necrosis factor to enhance anti-tumour immune response. In the mouse model of pancreatic cancer, TCR-T cells significantly slowed down the growth of tumours compared to the control group. The tumour size of the experimental group was smaller, while the tumour contained many more active TCR-T cells inside.

  Compared to direct modification of T cells, the research team believes that in the future, some vaccines can be designed to target cancer-restricting cryptic antigenic peptides. The vaccines could be injected to directly stimulate and ‘create’ tumour-targeting T-cells inside the body. These new ideas may be expected to help prolong the survival of pancreatic cancer patients and improve their quality of life.