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Therapeutic approaches focused on the inflammatory microenvironment are currently gaining more support, as biomolecules involved in the inflammatory colorectal cancer (CRC) tumor microenvironment are being explored. We analyzed tumor and paired normal tissue samples from CRC patients (n = 22) whom underwent tumor resection surgery. We assessed 39 inflammation-involved biomolecules (multiplex magnetic bead-based immunoassay), CEA and CA19-9 (ELISA assay) and the tissue expression levels of occludin and also pErk, STAT1 and STAT3 transcriptional factors (western blot). Tumor staging has been established by histopathological evaluation of HE stained tumor tissue sections. We report 32 biomarkers displaying statistically significant differences in tumor vs. control. Additionally, positive statistical biomarker correlations were found between MMP2–IL8 and BAFF–IL8 (Pearson correlation coefficients > 0.751), while APRIL–MMP2, APRIL–BAFF and APRIL–IL8 were negatively correlated (correlation coefficients < − 0.650). While APRIL, BAFF, IL8 and MMP2 did not modulate with tumor stage, they were inversely related to the immune infiltrate level and CD163 tissue expression. We conclude that the significantly decreased APRIL and increased BAFF, IL8 and MMP2 expression were tumor-specific and deserve consideration in the development of new treatments. Also, the positive correlation between Chitinase 3-like 1 and IL8 (0.57) or MMP2 (0.50) suggest a role in tumor growth and metastasis pathways. [ABSTRACT FROM AUTHOR]