IGLC3- tumor cells drive chemoresistance in colorectal cancer by polarizing SPP1+ macrophages via the CD44-Wnt-BTF3 axis

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with tumor heterogeneity and chemoresistance posing significant therapeutic challenges. In this study, we investigated the role of tumor-macrophage interactions in CRC progression. Using single-cell RNA sequencing (scRNA-seq) analysis from public database, patient-derived organoid models, and in vivo mouse models, we demonstrated that IGLC3 - tumor cells secreted TGF-β to polarize M0 macrophages into an SPP1 + , M2-like phenotype. These SPP1 + macrophages enhanced tumor cell proliferation, stemness, and migration via CD44–Wnt–BTF3 signaling pathway. Inhibition of CD44 or Wnt signaling with HH1 or a Wnt inhibitor effectively reversed macrophage-mediated chemoresistance and suppressed tumor growth and metastasis. Notably, HH1 exhibited superior safety compared to the Wnt agonist, making it a promising candidate for combination therapy. These findings provide novel insights into tumor heterogeneity and macrophage-mediated chemoresistance, highlighting actionable targets within the tumor microenvironment to improve CRC treatment outcomes.