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

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.