54 With survival at barely 5% at five years, glioblastoma remains one of the deadliest brain cancers. The first-line treatment consists of surgery to remove as much tumour tissue as possible. A team from the University of Geneva (UNIGE) and the Geneva University Hospitals (HUG) has now shown that this operation triggers a tissue repair process that makes the residual tumour even harder to combat. By administering lab-engineered immune cells, known as CAR-T cells, to mice before rather than after surgery, the team achieved unprecedented durable tumour control. The research, with significant clinical implications, is published in the journal Nature Communications. CAR-T cell therapies consist of collecting a patient’s own immune cells and engineering them in the laboratory so they can recognise, engage, and eliminate tumour cells. Until now, clinical trials testing CAR-T cells against glioblastoma have aimed to administer them after surgery. “However, the surgical procedure itself is not neutral, neither for the immune system nor for the tumour microenvironment, which will seek to defend the tumour against this assault,” explains Denis Migliorini, associate professor in the Department of Medicine and at the Translational Research Centre in Onco Haematology (CRTOH) of the UNIGE Faculty of Medicine, and Head of the HUG Neuro oncology Unit, who led the research. “We therefore wanted to investigate on the one hand, whether administering CAR-T cells before surgery changed treatment efficacy, and on the other, whether we could identify the most effective markers of immunosuppression.” Using two mouse models replicating closely the human disease, the scientists analysed the immune mechanisms at work in the tumour microenvironment with and without surgery, as well as their impact on tumour recurrence. “The tissue repair mechanism that sets in after surgery leads to the overexpression of the TREM2 protein, a marker of immunosuppressive macrophages, that is very strongly expressed in the tumour microenvironment. This protein reflects their level of activity and their ability to dampen the antitumour immune response,” explains Martin Pédard, senior research and teaching assistant in Migliorini’s team. “Thus, TREM2, already overexpressed in the tumour before surgery, further increases in response to the surgically induced wound and triggers a massive macrophage response that neutralises the immune cells fighting the cancer.” The team set out to test whether the infusion of CAR T cells before rather than after surgery could help avoid this hostile post-operative environment. They also developed CAR T cells specifically targeting TREM2 and deposited them directly into the cavity during surgery in a mouse model. Combined with another type of CAR T cell targeting tumour cells via the specific marker GD2, these cells were able to neutralise the immunity-suppressing macrophages. Administered before rather than after surgery, GD2-targeting CAR T cells retained their ability to attack the tumour and achieved far better disease control. Combined with the TREM2-targeting CAR T cells delivered into the resection cavity, they further extended survival. “CAR T cells shift the tumour towards an environment more favourable to the immune response, with more molecules promoting inflammation and tumour cell death,” describes Migliorini. The team then confirmed these observations in human tissue. Using a platform developed with the HUG neurosurgery and neuropathology divisions, they were able to culture tumour samples taken directly in the operating theatre and reproduce, in this tissue, the effect observed in mice. Glioblastoma is an aggressive form of primary brain cancer that grows rapidly and infiltrates surrounding tissue, making complete surgical removal difficult. Standard care typically involves maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Despite these interventions, recurrence is common, and outcomes remain poor. Immunotherapy approaches such as CAR T cells have transformed treatment for certain blood cancers but have faced major obstacles in solid tumours like glioblastoma, partly due to the highly immunosuppressive tumour microenvironment. These results could influence the design of future clinical trials. The Geneva team plans to open a first-in-human phase 1 trial next year for newly diagnosed patients. “This trial primarily aims to demonstrate the safety of CAR T cells after surgery and radio chemotherapy,” specifies Migliorini. “Based on our data, we will then be able to modify the protocol to include a trial in which CAR T treatments would be administered before surgery.” The findings highlight the importance of treatment timing and the role of myeloid cells in shaping responses to cellular immunotherapy. By addressing the post-surgical tissue repair process that amplifies immunosuppression through TREM2, the researchers have identified a potential strategy to improve the effectiveness of CAR T cells against this challenging disease. Further clinical investigation will be essential to determine whether these preclinical benefits translate to patients.