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and HC organoids to determine how cancer cells rewire their secretome, in samples directly derived from patient tissues.We integrate our secretomics datasets with clinical bulk and single cell RNA sequencing data to identify CRC-specific secreted proteins that mark immune excluded tumors.Results We observe a major rewiring of the secretome in the transition to malignancy, with 12-27% of all secreted proteins significantly altered between HC and CRC organoids.Notably, the secretome is markedly distinct between the immunologically divergent microsatellite stable (MSS) and instable (MSI) CRC subtypes, with NOTUM emerging as the top differentiating secreted protein.Cross-referencing our secretomics data with clinical datasets reveals that NOTUM expression is associated with decreased T cell infiltration across four independent datasets.In addition, we identify AZGP1 as a CRC-specific secreted factor associated with decreased infiltration of gamma delta T cells.Conclusion Overall, our study provides an in-depth characterization of the cancer cell-intrinsic secretome of MSS-CRC, and nominates NOTUM and AZGP1 as secreted factors that mark immune excluded tumors.This provides a framework to investigate the cell-intrinsic and -extrinsic regulators of secreted factors of interest to reveal novel immunotherapeutic targets.