Seminar: Activating the Early Tumour Immune Response: What is Missing? 

Abstract: T cell-based cancer immunotherapy has revolutionised treatment for haematologic malignancies. However, these same approaches largely fail in solid tumours. These tumours evade treatment through immunosuppressive microenvironments, antigen loss, and disrupted immune signalling. This highlights an urgent need for novel therapeutic strategies that can overcome these challenges. Our research goes beyond the adaptive-immune-centric paradigm by investigating innate immune pathways that shape early anti-tumour responses. We discovered that IL-33, an alarmin released during cellular stress, is frequently lost in metastatic cancers, suggesting a critical immune evasion mechanism. This observation led us to investigate type 2 innate lymphoid cells (ILC2s), tissue-resident innate immune cells that are dependent on IL-33 for activation and rapidly respond to tissue damage without requiring prior antigen exposure. Using single-cell RNA sequencing and spatial immunology, we demonstrate that ILC2s are dynamically recruited during early tumour growth, with inflammatory ILC2 subtypes enriched at invasive margins where they orchestrate local immune responses. Adoptive transfer experiments further support a role for ILC2s in reducing tumour burden and limiting metastasis. These findings position the IL-33/ILC2 axis as a promising therapeutic target to overcome the immunosuppressive barriers and establish a framework for harnessing innate immunity to improve cancer treatment outcomes.