Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro-computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 %ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 %ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80+ phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the formulation mainly results from sustained release of the chemotherapeutic payload in the tumor microenvironment. In addition, their high uptake by phagocytic immune cells encourages potential use for immunomodulatory anticancer therapy. Altogether, the beneficial biodistribution, efficient tumor targeting and prominent engagement of PEG-b-pHPMA-lactate-based CCPM with key cell populations underline the clinical versatility of this clinical-stage nanocarrier formulation.