Background Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by a highly immunosuppressive tumor microenvironment (TME) that facilitates immune evasion and tumor progression. Methods Integrated analysis of TCGA and GEO datasets was performed to evaluate CALB2 expression and its prognostic significance in CRC. Functional experiments including proliferation, migration, colony formation, and apoptosis assays were conducted following CALB2 knockdown. Co-culture assays and multiplex immunohistochemistry (mIHC) were used to assess TME remodeling. Results Elevated CALB2 expression correlated significantly with poor prognosis in CRC patients. CALB2 knockdown suppressed CRC cell proliferation, migration, and colony formation, while promoting apoptosis. CALB2 silencing also reprogrammed TME by inducing macrophage M1 polarization, enhancing CD8 + T cell cytotoxicity, and reducing immunosuppressive cell infiltration. Mechanistically, CALB2 activated the STAT3 signaling pathway to promote CCL5 secretion, facilitating M2 polarization of macrophages and activation of fibroblasts. Conclusion Our findings identify CALB2 as a critical regulator of tumor progression and immune escape in CRC, acting through dual oncogenic and immunomodulatory mechanisms. CALB2 represents a promising therapeutic target for enhancing immunotherapy efficacy in CRC.
Bian et al. (2026) studied this question.