Abstract Colorectal liver metastases grow following different histologic growth patterns (HGPs), classified as desmoplastic and nondesmoplastic (dHGP, non‐dHGP), being the latter associated with worst prognosis. This study aimed to investigate the tumor microenvironment (TME) between HGPs supporting different survival. Multiplexed immunohistochemical staining was performed with the Opal7 system in a 100‐patients cohort to evaluate the tumor–liver interface with three different cell panels: lymphoid, myeloid, and carcinoma‐associated fibroblasts. Differences between HGPs were assessed by Mann–Whitney U test with Pratt correction and Holm–Bonferroni multitest adjustment. Cytotoxic T‐cells were more abundant in tumoral areas of dHGP, while non‐dHGP had higher macrophages infiltration, Th2, CD163+, and Calprotectin+ cells as well as higher pSMAD2 expression. Regarding carcinoma‐associated fibroblasts, several subsets expressing COL1A1 were enriched in dHGP, while αSMAlow_single cells were present at higher densities in non‐dHGP. Interestingly, Calprotectin+ cells confer better prognoses in non‐dHGP, identifying a subgroup of good outcome patients that unexpectedly also show an enrichment in other myeloid cells. In summary, our results illustrate different TME landscapes with respect to HGPs. dHGP presents a higher degree of immunocompetence, higher amounts of Collagen 1 as well as lesser presence of myeloid cell populations, features that might be influencing on the better prognosis of encapsulated metastases.
