Interactions in the tumor microenvironment (TME) between tumor cells and stromal cells such as cancer-associated fibroblasts (CAF) favor increased survival, progression, and transformation of cancer cells by activating mechanisms of invasion and metastasis. The design of new therapies to modulate or eliminate the CAF phenotype or functionality has been the subject of recent research including natural product-based therapies. We have previously described the generation of a standardized extract rich in polyphenols obtained from the Cesalpinia spinosa plant (P2Et), which present antitumor activities in models of breast cancer and melanoma through activities that modulate the metabolism of tumor cells or induce the development of the immune response. In this work, a model of CAF generation was initially developed from the exposure of 3T3 fibroblasts to the cytokine TGFβ. CAF-like cells generated in this way exhibited changes in the expression of Caveolin-1 and α-SMA, and alterations in glucose metabolism and redox status, typical of CAFs isolated from tumor tissues. Then, P2Et was shown to counteract in vitro-induced CAF-like cell generation, preventing caveolin-1 loss and attenuating changes in glucose uptake and redox profile. This protective effect of P2Et translates into a decrease in the functional ability of CAFs to support colony formation and migration of 4T1 murine breast cancer tumor cells. In addition to the functional interference, the P2Et extract also decreased the expression of genes associated with the epithelial-mesenchymal transition (EMT) and functional activities related to the modulation of cancer stem cells (CSC) population. Therefore, a standardized polymolecular natural extract is presented here that has the potential to act on TME by interfering with the generation and functionality of CAFs.Funding Information: Ministerio de Ciencia, Tecnología e Innovación (Colciencias), Ministerio de Educación Nacional, Ministerio de Industria, Comercio y Turismo e ICETEX (792–2017) 2a Convocatoria Ecosistema Científico - Colombia Científica para la Financiación de Proyectos de I + D + i), World Bank and Vicerrectoría de Investigaciones, Pontificia Universidad Javeriana, Bogotá, Colombia (contract no. FP44842-221-2018).Declaration of Interests: S.F. is inventor of a granted patent related to P2Et. The rest of the authors declare no competing interests.