The abnormal physiology of the tumor microenvironment poses a challenge to the drug delivery in the tumor tissues. The dense tumor stroma hinders the movement of nanomedicine through the interstitium and negatively impacts their efficacy. In this study, hydroxychloroquine (HCQ) was investigated for its impact on alleviating the hindrance offered to the nanomedicine by extracellular matrix (ECM) components such as collagen and hyaluronan. In the current study, the effect of the antifibrotic activity of HCQ on bio-distribution and anticancer efficacy of systemically as well as locally (with the aid of injectable alginate hydrogel) administered liposomal doxorubicin was evaluated. In the in vitro model system, the HCQ treatment showed its antifibrotic potential by reverting the α-SMA