<p>Colorectal cancer (CRC) is one of the most common malignant tumors with high incidence and mortality. The challenge remains to construct reliable prognostic prediction models and to further elucidate the key molecular mechanisms of tumor progression. To address this, we performed WGCNA based on 120 immune cell expression profiles from GEO sources to obtain a collection of monocytes/macrophages-related genes. The prognostic model was constructed by univariate survival analysis and LASSO regression analysis. Then, the prognostic model was validated by Multivariate Cox regression, Kaplan–Meier survival analysis and ROC analysis. In this prognostic model, we identified that PLIN2 has a potential value for CRC prognosis. PLIN2 expression in monocytes/macrophages was verified by scRNA-seq datasets and spatial transcriptome datasets, and PLIN2 was found to promote macrophage transformation to M2 subtype. Clinical specimens and tissue microarrays confirmed the differential expression and prognostic value of PLIN2 in CRC patients. Functional experiments demonstrated that PLIN2 gene overexpression promoted the proliferation, migration and invasion of CRC cells and significantly facilitated tumor growth in vivo. Mechanistically, we revealed that CD36 is a potential downstream target gene of PLIN2. The CD36 inhibitor Sulfo-N-succinimidyl Oleate significantly reversed PLIN2-induced proliferation, migration, invasion, and EMT activity of CRC cells in vitro and in vivo. Immunoprecipitation and immunofluorescence experiments confirmed that PLIN2 could interact with CD36. PLIN2 stabilized CD36 protein expression by inhibiting the proteasomal degradation pathway, thereby promoting CD36-mediated EMT activity. Overall, our study highlights that the PLIN2/CD36 axis regulates EMT activity and CRC progression, suggesting that interventions in this signaling pathway may offer a promising therapeutic approach to CRC progression.</p><p></p>