Cancer immunotherapies represent an emerging forefront in the treatment of various terminal malignancies. Unfortunately, existing single-arm and combinations of immunotherapies for microsatellite-stable colorectal cancer (MSS-CRC) are poorly efficacious due to the low tumour mutational burden and an immunosuppressive tumour microenvironment. An emerging strategy to elucidate novel immune-druggable targets involves characterising the "surfaceome", as the cell membrane is a crucial and therapeutically accessible interface. Here, we focused on deconvoluting the MSS-CRC "surfaceome" for novel immunotherapeutic target identification by performing extracellular biotinylation of intact patient-derived MSS-CRC organoids and quantitative proteomics on affinity-enriched surface proteins, comparing healthy, primary and metastatic MSS-CRC. From a total pool of 487 highly confident surface proteins, we first demonstrate the reliability and clinical relevance of our dataset through the detection of high levels of prominent CRC progression markers CDH17, LY75 and CA9. Importantly, we shortlisted 2 potential targets DPEP1 and SCARB1 which displayed differentially upregulated protein expression in primary MSS-CRC and further validated using tissue microarray and gene silencing approaches. The discovery of these new MSS-CRC-specific prognostic markers can potentially guide clinical staging and disease stratification in a multi-biomarker panel setting. By adopting an empirical biochemical approach, we ultimately aim to progress targeted therapeutic strategies in MSS-CRC. The success achieved here could also be directly applied extensively to study other forms of advanced solid tumours, and tumour subtypes.