A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer.

Immunotherapy remains largely ineffective in colorectal cancer (CRC), particularly in microsatellite stable (MSS) tumors, which represent the majority of cases. However, the complexity of intratumoral heterogeneity has made it difficult to define tumor-intrinsic programs that drive immune resistance. Here, we identify a cancer cell population that emerges predominantly in advanced-stage MSS CRCs. These cells exhibit stem-like features but aberrantly activate a WNT-inhibitory transcriptional program marked by high NOTUM expression. We term these cells WNT/β-catenin inhibitory cancer cells (WICCs). WICCs are enriched in immune-excluded tumors, correlate with reduced CD8+ T cell infiltration, and are induced in both primary human CRC tumors and patient-derived tumoroids. Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8+ T-cell-mediated cytotoxicity, uncovering a tumor-intrinsic mechanism of immune evasion and nominating the WICC-NOTUM axis as a selective and tractable therapeutic target to overcome immunotherapy resistance in CRC.