Abstrata

In normal tissue, resident macrophages have site-specific phenotypes, for example, microglia in the brain, Kupffer cells in the liver, alveolar macrophages in the lung, and peritoneal macrophages in the gut. These tissue-resident macrophages likely arise from embryonic precursors and are maintained by self-renewal [8]. However, all these macrophages display a common and principal role in maintaining steady-state homeostasis. On the other hand, monocytes from the blood are recruited and transformed into mature macrophages in specific tissues, in response to cytokines and chemokines released during inflammation. Depending on the microenvironment, macrophages are differentiated into either classical activated (M1/Th1-activated) macrophages or into alternatively activated (M2/Th2-activated) macrophages.

Within tumors, macrophages can be in between or off the spectrum of the M1/M2 states depending on the tumor stage. These TAMs can be derived from resident macrophages [19] or attracted from bone marrow and spleen to the tumor site thanks to the CCL2 (MCP-1) and CCL5 (RANTES) chemokines produced by the tumors, fibroblasts, endothelial cells, and even by the TAMs themselves .Colony-stimulating factor-1 (CSF-1) is also a monocyte/macrophage attractant, as well as a macrophage survival and polarization signal, which is highly important in tumors. Early in tumor development, M1 macrophages are able to kill and remove tumor cells, and to produce cytokines for the recruitment and activation of other immune effector cells Nevertheless, the evolution of the TME, depending on the stage of the tumor and on the type of cancer, can revert this anti-tumor program and favor a switch of infiltrated macrophages into an M2 phenotype with pro-tumor and immune-suppressive functions. Pro-tumor functions of TAMs are the result of a macrophage polarization with a particular cytokine profile (macrophage colony-stimulating factor (M-CSF), IL-4, IL-13, IL-10, Prostaglandin E2 (PGE2)) of the TME [24]. However, chemokines and signals in the TME originating from tumor cells, B-cells, and stromal cells (e.g., CSFs, TGF-β, IL-1) can deviate macrophage functions and phenotype, astray from the classical M1/M2 polarized cells. These nanostructures' primary advantages for biomedical applications are the small size within the same scale than that of biomolecules and an augmented area-to-volume ratio allowing an increased interphase area in a small. One crucial advantage of nanoparticles for cancer therapy is their tendency to naturally accumulate within tumors via enhanced permeability retention. The fundamental features of EPR are hyperpermeability of tumor vasculature to large particles (enhanced permeability) and impaired lymphatic drainage, retaining the particles into the interstitial space of the tumor .This way, nanomaterials passively accumulate at tumors' sites where they can then exert their therapeutic/diagnostic effect. In order to extravasate the vasculature and avoid renal filtration and liver capture, nanoparticles should range between 10 and 100 nm and preferably present a neutral or anionic charge. Using the EPR to passively accumulate nanoconjugates at the tumor site has been thoroughly described in a general way. However, tumors are heterogeneous, impacting the capacity of nanoparticles to homogeneously penetrate the neoplastic tissue.

Despite the growing knowledge of tumor development and progression, it is virtually impossible to determine cause-effect chain of events, from the initial stage when cells become tumorigenic and initiate uncontrolled proliferation, to a mature high-grade tumor. Sometimes one is tempted to associate one event triggered by proliferating tumor cells to an event occurring within the TME, but this correlation falls far from reality since it is the evolving interplay of all TME components that ultimately will be responsible for tumor modulation and progression (Hanahan and Weinberg, 2011; Netea-Maier et al., 2018). Here we shall focus on each component of the TME separately for simplicity. However, it is crucial to understand that each one of these events, occurring for each component, may be triggered in a different way for a different tumor or tumor type, thus affect all the other TME components differently, and consequently resulting in different outcomes. Figure 1 and Table 1 highlight the major events occurring at the TME that contribute for tumor progression.

Conclusion & Significance: This implementation of LOX for a functionally responsive nanoparticle could extend to applications such as oncolytic virotherapy or clinical clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) systems using AAV2 system.