Background and Aims Colorectal cancer liver metastases (CLM) have different histopathological growth patterns (HGP), among which replacement HGP (RHGP) is closely associated with vessel co-option, which directly affects the effect of anti-angiogenic therapy and leads to poor prognosis. Therefore, this study was conducted to investigate the molecular pathological features of HGP, so as to provide a basis for the study of the molecular mechanism of CLM.Methods The clinical data and paraffin-embedded specimens of 103 patients with CLM undergoing surgical resection between 2010 to 2020 in the Department of General Surgery of Xiangya Hospital, Central South University were collected, in which 58 cases were desmoplastic HGP (DHGP) and 45 cases were RHGP. The correlation between RHGP and clinicopathologic factors of CLM patients was assessed based on the international HGP consensus guidelines. The associations of RHGP with vessel co-option and WAVE2 were analyzed through immunohistochemical staining for the protein expressions of WAVE2 and CD31. The correlation between WAVE2 and immune infiltration was analyzed using TIMER2.0 database. WAVE2 interaction signaling molecules were analyzed by KEGG database.Results HGP was significantly associated with the time to liver metastasis occurrence and lymph metastasis (both P<0.05). The CD31 positive rate was 27.5% and 37.0% in DHGP group and RHGP group, and high WAVE2 expression rate was 58.6% in DHGP group and 82.2% in RHGP group respectively, and the differences had statistical significance (P=0.023, P=0.011). WAVE2 expression was significantly correlated with B cells (r=0.258, P=1.41e-07), CD4+ T cells (r=0.467, P=3.67e-23), CD8+ T cells (r=0.318, P=5.47e-11), and neutrophils (r=0.407, P=2.02e-17), macrophages (r=0.301, P=6.63e-10) and dendritic cells (r=0.438, P=3.01e-20) immune infiltration. WAVE2 expression was significantly positively associated with CTTN (r=0.454, P=1.26e-24), HDAC4 (r=0.54, P=5.43e-36), CYFIP1 (r=0.39, P=4.24e-18), CDC42 (r=0.443, P=2.12e-23), PDGFB (r=0.316, P=4.25e-12), PRKACA (r=0.363, P=1.05e-15), and other downstream molecules.Conclusion WAVE2 expression may be involved in the formation of RHGP by promoting the migration of colorectal cancer cells and regulating vessel co-option and tumor immune microenvironment.