Abstract
Secreted factors are essential mediators of cellular communication that are exploited by tumors to control their environment and evade immune attack. However, how cancer cells rewire their secretome is unclear due to challenges in reliably profiling cancer cell-specific secreted factors. Here, we apply a click chemistry-based approach to selectively profile the secretome of patient-derived colorectal cancer (CRC) and healthy colon organoids. We observe cancer cell-intrinsic rewiring of the secretome during malignancy, with clear separation between microsatellite stable (MSS) and instable cancers. We then leverage this secretomics dataset to identify secreted factors that mark immune-excluded cancers, revealing NOTUM as a marker of decreased T cell infiltration across four independent datasets. Overall, our study provides an in-depth characterization of the cancer cell-intrinsic secretome of MSS-CRC and nominates NOTUM as a secreted factor marking immune-excluded colorectal cancers. This provides a scalable framework to link cancer cell-derived secreted factors to relevant tumor phenotypes.