Abstract Purpose: The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment. Experimental Design: A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblasts’ activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor–stroma interaction. Finally, we tested, in vivo, the blockade of the tumor–stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin. Results: IL1β/TGFβ1 are the triggers for fibroblasts’ recruitment and conversion into carcinoma-associated fibroblasts (CAF) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumor cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralizing IL1β antibody and a TGFBR1 inhibitor is relieved by the TAK1-mediated activation of the noncanonical TGFβ pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumor cells. TAK1 plus TGFBR1 inhibition blocks IL1β/TGFβ1-mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumor cells became more sensitive to chemotherapy. In vivo, the combination of a TAK1 inhibitor plus TGFBR1 inhibitor reduced the metastatic capacity of tumor cells and the recruitment of fibroblasts. Conclusions: Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.