Recent studies show that secreted phosphoprotein 1 (SPP1) is linked to the progression of various cancers, including colorectal cancer (CRC). SPP1 also promotes M2 macrophage polarization, contributing to immune evasion in the tumor microenvironment. Tetrahydrocurcumin (THC) has been reported to alleviate CRC, but the mechanism remains unclear.The study aimed to explore how THC modulated the SPP1/CD44 axis to inhibit M2 polarization and suppress CRC development.Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model was used to assess the anti-CRC effects of THC. Transcriptome sequencing was conducted to identify the key targets of THC in CRC. The effects of THC on CRC cells were evaluated by CCK-8, colony formation, migration assays, immunofluorescence staining and flow cytometry. Human monocytic cells, THP-1, and colon cancer cell line, HCT116, were co-cultured, both directly or indirectly, to mimic the tumor-macrophage interactions, and investigate the role of SPP1/CD44 axis and the intervention effect of THC.THC significantly inhibited CRC carcinogenesis in mice and improved pathologic symptoms, serum inflammatory markers, and intestinal barrier integrity. THC inhibited CRC cell proliferation, migration and colony formation, while promoting apoptosis. Transcriptome analysis identified SPP1 as a key target of THC against CRC. SPP1 facilitated CRC progression by activating the ERK signaling pathway and maintaining the M2-like phenotype of macrophage, which further exacerbated this response. THC inhibited CRC development by targeting the SPP1/CD44 axis, rather than the integrin pathway.SPP1 played a crucial role in maintaining the M2 phenotype of macrophage and promoting CRC cells proliferation. THC inhibited the activation of ERK signals in CRC cells and phenotypic transformation of M2-like macrophages through the SPP1/CD44 axis, thereby regulating the tumor immune microenvironment to exert anti-CRC effect.Copyright © 2025 Elsevier GmbH. All rights reserved.