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Abstract

Tumor-associated monocytes and macrophages accumulate in colorectal cancer (CRC) and play a critical role in shaping the tumor microenvironment (TME). While they have been linked to both pro- and anti-tumor functions, understanding the cues that instruct the phenotype of individual subsets, as well as their functional impact on the TME remains challenging. In this study, I established co-cultures comprising primary human monocytes and patient-derived organoids (PDOs) from CRC tumors to emulate myeloid cell-carcinoma interactions in vitro. Across diverse PDOs, monocytes acquired a shared phenotype that transcriptionally resembled IL1B-programmed monocytes previously identified in CRC patients. This phenotype emerged independently of the tumors’ mutational profiles or CMS type, and was arising by carcinoma cell contact without the need for additional stromal components. At the mechanistic level, I demonstrated that soluble mediators secreted by PDOs were sufficient to induce the expression of IL1B signature genes such as the chemokines CXCL2, CXCL5, and CXCL7. In parallel, phagocytic uptake of tumor debris reduced the expression of MHC class II molecules on the surface of myeloid cells, suggesting an impairment of antigen-presenting capacity. In addition, this in vitro system allowed the functional assessment of PDO-exposed monocytes demonstrating a compromised capacity to mount an inflammatory response upon TLR stimulation. This uncoupling of gene expression from effector function points to a refractory state of monocytes upon contact with carcinoma cells, potentially contributing to an immune evasive TME where tumor-derived inflammation is maintained at a transcriptional level but fails to translate into effective anti-tumor activity. Together, my PDO–myeloid cell co-cultures offer an elegant model system to study the interplay between human epithelial cancer cells and monocytes, and to advance the understanding of myeloid plasticity and function in CRC. Future studies can leverage this model to identify and validate therapeutic strategies aimed at overcoming monocyte/macrophage dysfunction, for instance by restoring antigen presentation, breaking refractoriness to innate stimuli, or selectively targeting IL1B-driven inflammatory programs. By capturing the personalized interplay between patient-derived tumor cells and primary immune cells, this system bridges experimental modelling and clinical heterogeneity, thereby advancing the development of TAM-based therapies with improved bench-to-bedside translation for CRC patients.