Targeting canonical Wnt/β‐catenin signaling by PORCN inhibitors or RSPO3 blockage leads to rapid and sustained tumor regression but also induces serious side effects.[17, 18, 19] Here, small‐molecule inhibitor tegatrabetan targeting β‐catenin showed desirable anti‐tumor activity but high toxicity in normal colorectal organoids. Here, RSPO3 is linked to neoplasm.