91 “Build your enemy a golden bridge to retreat across.” This advice from Sun Tzu’s The Art of War may seem far removed from the fight against cancer, but a new study has shown that cancerous tumours adopt a similar strategy in their battle against the immune system. Researchers from the Weizmann Institute of Science, led by Professor Idit Shachar, have uncovered how a specific type of aggressive breast cancer fosters immune suppression by prompting nearby cells to build molecular bridges. This insight could pave the way for new, more effective treatments targeting the tumour’s microenvironment rather than the cancerous cells themselves. The study, published in Cell Reports, reveals how molecular bridges formed between immune cells in the tumour environment allow cancer to evade detection and destruction. These findings are the culmination of years of research into the communication between cancer cells and their surrounding support cells, which play a critical role in the development and progression of tumours. In the past, cancer treatments largely focused on destroying malignant cells using radiation or chemotherapy. But over recent decades, scientists have realised that tumours thrive not only because of the cancer cells themselves but also due to the interactions they have with nearby non-cancerous cells. Prof. Shachar and her colleagues had previously shown that blood cancer cells create similar bridges between themselves and supportive cells, using a protein known as CD84 (SLAMF5). This protein facilitates the creation of intercellular bridges, allowing the cancer cells to survive and proliferate. Building on these earlier findings, Shachar and her team, in collaboration with the City of Hope Cancer Centre in California, turned their attention to other forms of cancer, including triple-negative breast cancer. This particular type of breast cancer is notoriously difficult to treat due to its lack of distinguishing markers that allow for targeted therapies. Instead of attacking the cancer cells directly, the researchers sought to focus on the tumour’s microenvironment, where supportive cells play a key role in protecting the tumour from immune responses. In their recent study, the researchers analysed genetic sequences from growths taken from women with triple-negative breast cancer and discovered that CD84 expression in the tumour microenvironment was much higher than normal. Even though breast cancer cells themselves express low levels of CD84, the cancer cells induce nearby immune cells to overexpress the protein, leading to the formation of molecular bridges that suppress the immune response. The team also found that patients with higher levels of CD84 in their tumours had poorer survival outcomes. Next, the researchers studied the progression of breast cancer in mice genetically engineered not to express the CD84 protein. These mice developed significantly smaller tumours, prompting the scientists to test their previously developed antibody, which had successfully blocked molecular bridge formation in blood cancers, as a treatment for breast cancer. When administered to mice with developing breast cancer, the antibody significantly slowed tumour growth and, in some cases, led to complete recovery. The study also uncovered the role of regulatory B cells in breast cancer. These immune cells, which normally suppress the immune system, were found to build more molecular bridges in a breast cancer environment than in healthy tissue. This bridge formation led the B cells to produce a small protein known to suppress the immune response. This protein interfered with the activity of T cells, the immune system’s primary defenders against cancer, preventing them from attacking the tumour. Building on these discoveries, the City of Hope cancer centre, together with Yeda Research and Development, the commercial arm of the Weizmann Institute of Science, formed Slam Biotherapeutics. The company focuses on developing cancer treatments based on anti-SLAM family antibodies. Prof. Shachar explained that the antibody they developed is effective only on cells that express a high level of CD84. In healthy individuals, most cells do not express this protein at high levels, making the treatment specific to the tumour microenvironment. Although the antibody has shown promise in treating blood cancers, the new findings open the door for its use in other types of cancers, including those where the cancerous cells do not express high levels of CD84. “By focusing on the tumour microenvironment, we are offering a treatment that could help a wide range of patients, opening the door to a new era of personalised cancer therapies,” said Professor Shachar.