In the realm of oncology, immunotherapy has evolved as a powerful modality to treat several cancer types. Yet, heterogeneity in response and the problem of resistance remain critical challenges especially in pancreatic ductal adenocarcinoma (PDAC). Transforming Growth Factor-beta (TGF-beta) and Activin, members of the TGF-beta superfamily, are pivotal signalling pathways implicated in tumorigenesis, immune regulation, and therapy resistance. However, the precise roles these pathways play in mediating immune escape and immunotherapy resistance are still poorly understood. This research proposal aims to delineate the interplay between TGF-beta and Activin signalling pathways in the tumour microenvironment (TME) and explore how they modulate response to immunotherapy in PDAC. We propose to: 1) Investigate the role of TGF-beta and Activin in immune cell recruitment and function within the TME. 2) Characterize how alterations in these pathways correlate with immunotherapy resistance. 3) Evaluate the therapeutic efficacy of targeted inhibitors against TGF-beta and Activin pathways in combination with immunotherapy, using in vitro and in vivo cancer models. Methodologies to be employed include mouse models of PDAC, multiplex immunofluorescence, single-cell RNA sequencing using 10X Genomics, CRISPR/Cas9 gene editing, NanoString GeoMx technology for comprehensive spatial profiling and multimodal intersection analysis. These cutting-edge techniques will provide a multi-dimensional view of the cellular and molecular complexities involved. The study is designed to foster collaborative interdisciplinary research, engaging with both academic institutions and industry partners like AstraZeneca. Insights from this research could open new avenues for rational drug design and combination therapies with the potential to increase the effectiveness of current immunotherapeutic regimens. Ultimately, the findings aim to facilitate more effective treatment paradigms for cancer patients.