Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence
Yannik Kaiser, Christopher Garris, Eliana Marinari, Hyung Shik Kim, Juhyun Oh, Martin Pédard, Elias A. Halabi, Moonhyun Choi, Sepideh Parvanian, Rainer H. Köhler, Denis Migliorini, Ralph Weissleder
Abstract
Abstract Glioblastoma is a highly aggressive brain tumour with a high risk of recurrence after surgery, even when combined with chemotherapy and radiotherapy. A major barrier to lasting treatment is the tumour’s immunosuppressive environment, which is largely dominated by myeloid cells. Here we describe the development of a biodegradable implant to sustainably release immune-modulator small molecules to reprogram tumour-infiltrating myeloid cells toward a pro-inflammatory, antitumour phenotype in the surgical cavity after tumour removal. In immunocompetent mouse models, this therapy induces interleukin-12 expression in myeloid cells without systemic cytokine elevation, and increases the infiltration of CD8 + and CD4 + T cells. Over 50% of mice treated (in combination with radiotherapy and chemotherapy) remain tumour-free during the experimental course (80 days). We further treated human glioblastoma explants ex vivo with the therapy and observed increased interleukin-12 expression in tumour-infiltrating myeloid cells, supporting the translational potential of this strategy. This implantable system offers a promising approach to prevent glioblastoma recurrence by activating innate immunity and sustaining immune surveillance post-surgery.