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tumor-associated macrophages (TAMs), have a dual role in influencingnanotherapeutic efficacy. TAMs exhibit high plasticity and can adopt eithera pro-inflammatory (M1) or an anti-inflammatory, pro-tumoral (M2)phenotype. In their M2 state, TAMs promote tumor growth, angiogenesis,and immunosuppression, thereby creating a challenging environment foreffective therapy. Furthermore, TAMs can internalize nanoparticles throughphagocytosis, resulting in their sequestration and premature clearance,which diminishes therapeutic efficacy. Nevertheless, nanoparticles can beengineered to leverage TAMs for drug delivery by selectively targeting TAMsto deliver therapeutic agents or reprogramming M2 TAMs into an M1phenotype, thereby enhancing anti-tumor immunity. Other immune cells,such as dendritic cells, neutrophils, and T-cells, also interact withnanoparticles in ways that can either augment or impair therapeuticoutcomes. Modulating these interactions in state-of-the-art vitro 3D tumormodels will be increasingly required to account for their impact onnanotherapeutics performance. 4. 3D IN VITRO TUmOR mODeLs fOR NANOTheRAPIes sCReeNINGIn the last decade, 3D in vitro tumor models have emerged as highlyvaluable platforms for screening nanotherapies. Comparing to simplisticcell cultures, such models are able to recreate a more physiologicallyrelevant tumor microenvironment (TME), closely emulating gene expressionpatterns, cell-cell interactions, nutrients and oxygen transport limitations,and the spatial organization found in vivo. In fact, preclinical 3D platformscan provide important insights regarding the evaluation of the efficacy ofnanocarriers- delivery systems and the impact of TME on drug response, aswell as study and predict the penetration and distribution of such agentswith 3D malignant tissues (Figure 1).In recent years, conventional cancer therapies have undergone aconsiderable evolution, as they have demonstrated to be insufficient asstandalone treatment for achieving a favorable patients%u2019 outcome.Recently, several other therapies approaches (e.g., immunotherapy,nanotherapy, etc.) have been implemented as adjuvant therapies of thetraditional ones. Nanotherapies, in special, have emerged as a promisingadjuvant approach in cancer treatment, offering several advantages suchas the enhancement in the efficacy of existing cancer treatments whilepotentially reducing side effects and overcoming drug resistance. However,major barriers to the therapeutic efficacy of nanomedicines remain,essentially based on their low selectivity and undesirable side effects. Inrecent years, there have been reports of rationally developed112Potential of 3D tumor models for nanotherapies pre-clinical screeningVitor M. Gaspar1, Jo%u00e3o F. Mano, et al.