Background <p>The heterogeneity of tumors significantly impacts on colorectal cancer (CRC) progression. However, the influence of this heterogeneity on the spatial architecture of CRC remains largely unknown.</p> Methods <p>Spatial transcriptomic (ST) analysis of AOM/DSS-induced colorectal cancer (CRC), integrated with single-cell RNA sequencing, generated a comprehensive spatial atlas of CRC. Pseudotime trajectory, stemness evaluation, and cell-cell communication analyses explored how CD44⁺ tumor cells at the leading edge remodel the tumor microenvironment (TME). In vitro experiments and immunofluorescence staining of clinical samples validated pleiotrophin (PTN) signaling in promoting cancer-associated fibroblasts (CAFs) phenotypic transition and CRC progression.</p> Results <p>Our findings revealed a distinctive layered ring-like structure within CRC tissues, where CD44⁺ tumor cells exhibiting high stemness were positioned at the tumor’s leading edge. Inflammatory CAFs (iCAFs)-like, myofibroblastic CAFs (myCAFs)-like cells and pro-tumorigenic neutrophils primarily located at the tumor edge, in proximity to CD44⁺ tumor cells. CD44⁺ tumor cells then triggered the phenotypic transition of CAFs into iCAF-like and myCAF-like cells through PTN signaling.</p> Conclusions <p>Our results provide distinctive insights into how tumor heterogeneity reshapes the TME at the leading edge of tumor, thereby promoting CRC progression.</p>