Next-generation colorectal cancer microecosystems for the discovery of microbiome-driven immunotherapies in personalized settings

Colorectal cancer (CRC) ranks among the most prevalent and lethal malignancies globally. However, efforts to translate CRC research findings into clinical advancements have been hampered by inadequate in vitro systems. Even the current gold standard organoid models remain severely limited as they lack the topobiological complexity required to fully capture CRC pathobiology ex vivo. Among other factors, their unsuitability to properly model the multifaceted interactions between CRC and its tumor microenvironment (TME) is particularly limiting, especially since the TME has emerged as an essential element to tumor biology. Crucially, while the TME is being successfully exploited for immunotherapy in many cancers, these therapies remain ineffective in more than 90% of CRC patients. Among the different components of the TME, the colon microbiota is particularly interesting for CRC tumor immunity as in vivo evidence indicates that it can regulate inflammation, modulate immune cell activity, and alter responses to immune checkpoint inhibitors. However, whether anti-tumor immunity can be enhanced through targeted microbiomal-based therapies in CRC patients not responsive to immunotherapy has not been approachable in vitro due to the lack of suitable models. Building upon our expertise in microfluidics, tissue engineering, cell biology, and multiomic technologies, we aim to develop a groundbreaking ex vivo platform capable of integrating complex lymphoid and microbiomal microenvironments in patient-specific tissue-engineered miniature colons. This TME-oriented cancer model will reconstruct functional interactions among diverse components of the TME with unparalleled pathophysiological intricacy. It will be primarily used to shed light on the cancer–microbiota–immune axis, aiming to discover opportunities to harness microbiomal components for improving anti-cancer immunity in CRC. We envision that this project will pave the way towards personalized oncology approaches.