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3.UNCOveRING The ImPACT Of TUmOR mICROeNvIRONmeNTCOmPONeNTs ON NANOTheRAPeUTICs sCReeNINGCurrently, nanotherapeutic clinical outcomes remain still poor, with only afew nanotherapies, (i.e. immunotherapies and adjuvant peptidesconjugates), showcasing significant improvements in patient outcome. Thehigh-rate of failure observed in nanocarriers and other nanotherapies canbe partially attributed to the complexity of parameters available to tunein nanotherapies development coupled to the lack of specificity to tumorsites and patient stratification in clinical assays. Moreover, the TME posessignificant challenges to the effective delivery and uptake of bothsystemically administered nano-scale therapeutics and traditionalchemotherapeutic agents. The complex and heterogeneous TME of solid tumors, is characterized bydysregulated cellular communication, as well as limited blood andlymphatic vascularization restrict flow to and from the tumor, while theabnormally dense ECM obstructs interstitial transport. As a result, solidtumors often exhibit hypoxic and necrotic regions, an accumulation ofmetabolic waste that contributes to an acidic extracellular pH, andelevated interstitial fluid pressure (IFP). The complex sets of varyingparameters and tumor landscapes difficult preclinical experimentationrequiring the utilization of advanced models capable of representingspecific microenvironmental phenomena. Overall, a deep understanding of the transport processes and TMEassociated barriers associated to nanotherapeutics delivery are importantfeatures to take into consideration when modelling in vitro cancer modelsfor nanotherapies screening, with their recapitulation leading to theestablishment of promising platforms for future nanomedicines design andclinical translation.3.1. Tumor vasculatureIn the context of tumor dysregulation, angiogenesis can be hijacked withabnormal vessel formation being promoted and coordinated by cancer cellsand cancer-associated (CA) populations of cells (e.g., CA-mesenchymalstem cells, CA fibroblasts, CA-pericytes, and other altered immunepopulations). Consequently, tumor vasculature becomes highlydisorganized, with some solid tumor regions experiencing hypervascularization while others remain under-vascularized. Abnormally formedtumor-vasculature presents irregular hierarchical arrangements, with109 Nanomaterial y NanomedicinaMar%u00eda Vallet , Antonio J. Salinas