The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, has been shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. We here investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM). Under control conditions, we found higher levels of Cy7-CCPM in PANC-1 tumors (16.7 % ID g at 48 h post i.v. injection) than in 4T1 tumors (11.0 % ID g). In both models, free and nano-formulated TMX failed to improve CCPM delivery. These findings were congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicated that TMX treatment did not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, our results demonstrate that in PANC-1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor-targeted drug delivery.