2.2.2. Nanoparticles to Target Immune TME (iTME)

Very nice and comprehensive reviews related to this topic have been recently published [31,39]. Overall, a lot of different strategies exist in order to target immunity within the TME, especially through its immunosuppressive properties.

The most studied immunosuppressive strategy relies on the inhibition of immune checkpoints, especially in a clinical context with the use of monoclonal antibody-based ICIs targeting CTLA-4, PD1, and PD-L1 [3]. So far, various NPs (organic/inorganic) have been designed with success to deliver ICIs (e.g., siPD-L1, anti-PDL1, anti-PD1, and anti-CTLA-4) in preclinical models [38]. Many other ways to target the immune checkpoints synergistically with ICIs have been performed in combination with various therapeutic modalities such as photothermal therapy (PTT), photodynamic therapy (PDT), radiodynamic therapy, sonodynamic therapy, genetic manipulations, and stimulatory agonists [31]. Another way to remove immunosuppression of the TME is to target indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme producing immunosuppressive metabolites. This enzyme has been shown to be overexpressed in many cancers and many inhibitors have been designed so far. In this context, a prodrug nanoplatorm (approximately 40 nm) has been designed by integrating a PEGylated IDO1 inhibitor (epacadostat) and a photosensitizer (indocyanine green, ICG). Both in vitro and in vivo (B16-F10 cells), the authors demonstrated good efficacy of this strategy, especially in combination with PD-L1 checkpoint blockade [40]. Another way to remove immunosuppression is to reprogram immunosuppressive cells such as M2-like TAMs (*vide infra*) and MDSCs. Phuengkham et al. have targeted both TAMs and MDSCs. They encapsulated resiquimod (TLR7 and 8 agonist) and doxorubicin (to induce ICD) within crosslinked collagen-hyaluronic acid scaffolds. Interestingly, there was subsequent polarization from M2-like to M1-like TAMs associated with the reprogramming of MDSCs into tumor-killing APCs [41].

Another relevant strategy relies on the activation of DCs with nanomedicines. Since DCs are essential to the initiation of the anti-tumor immune responses through the CIC, stimulating their activation has attracted a lot of attention lately. The first strategy to activate DCs is the agonism of the stimulator of interferon genes (STING), a cytosolic receptor mainly localized in the endoplasmic reticulum. When the innate immune system detects DNA from viruses or tumors, cGMAP (an agonist of STING) is produced and activates cells such as DCs, which in turn release type I Interferon (IFN-I). To mimic this mechanism, Wang-Bishop et al. developed a polymeric NP ("polymersome") encapsulated with cGMAP. These STING-activating NPs were able to induce the expression of IFN-I through DCs stimulation. This was associated with ICD, a remodeling of iTME, and a subsequent inhibition of the tumor growth in neuroblastoma tumor-bearing mice [42]. Another approach to activating DCs relies on cancer vaccines (cellular, protein/peptide, and genetic vaccines), through the use of various NPs. This topic has been recently and extensively reviewed [43].
