AbstractIn this study, we show that a negatively charged biodegradable nanoparticles, CNP-301, have strong anti-tumor activity in several tumor models. This effect appears to be driven by shifting polarization of tumor associated macrophages (TAMs) to an anti-tumor M1 type and by downregulation of pro-tumorigenic cancer associated fibroblasts. Moreover, we show that CNP-301 treatment induces apoptosis of cancer associated fibroblasts (CAFs) in the tumor supporting a mechanism where perturbations of the TME and the associated stroma results in anti-tumor effects.