Conventional chemotherapeutics for colon cancer often fail to achieve optimal clinical outcomes, as many patients develop resistance and experience significant toxicity, thereby increasing the overall health burden. Understanding the mechanisms conferring resilience to cancer cells is essential for developing more effective therapies. 5-Flourouracil (5FU) is the standard of care used for colon cancer. 5FU-associated inflammation, characterized by a change in cytokine profile, enables the colon cancer cells to evade cell death, thereby undermining the cytotoxic effects of the drug. Current study underscores the significance of CCL20 signaling, which is linked to inflammatory conditions and is elevated during colon carcinogenesis, in tempering the cytotoxic effects of 5FU. The presented data demonstrate an inverse correlation between CCL20 concentrations in colon cancer and sensitivity to 5FU. Moreover, treatment with 5FU further stimulates CCL20 signaling in colon cancer cells, likely via increased fatty acid efflux. Notably, the findings reveal that IL10 signaling is under negative regulation of CCL20. Additionally, exposure to 5FU elevates IL10 levels, thus creating a complex interplay of pro-inflammatory and anti-inflammatory pathways. Such dual activation of contrasting mechanisms undermines the therapeutic efficacy of 5FU. Therefore, the insights gained from this study emphasize the significance of addressing immune signatures characterized by CCL20 and IL10 to enhance the effectiveness of 5FU in colon cancer treatment.