*3.2.3 Targeted modulation of tumor-associated myeloid cells (TAMCs)*

To enhance the therapeutic effects of ICT and modulate the immunosuppressive TME, various approaches have been adopted for TAMCs targeting. As is known, polarization of macrophages in TME into M2 tumor-associated macrophages (TAMs) can facilitate tumor progression and inhibit antitumor efficacy of ICT by releasing anti-inflammatory cytokines and angiogenic factors. Based on this, Choo et al. exploited M1 macrophages derived nanovesicles (M1NVs) to repolarize M2 TAMs to M1 macrophages which can release pro-inflammatory cytokines and elicit antitumor immunity [34]. The results showed combination treatment of M1NVs and aPD-L1 significantly decreased the tumor volume compared to the treatment of M1NVs or aPD-L1 alone, proving that M1NV can repolarize M2 TAMs to M1 macrophages and potentiate the antitumor efficacy of ICT. Shae et al. constructed stimulator of interferon gene NPs (STING-NPs) based on endosomolytic polymersome possessing pH-responsive membrane [35]. The STING-NPs can enhance cytosolic delivery of 2′3' cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which is an endogenous ligand for cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING). They demonstrated that STING-NPs treatment could remodel the TME and repolarize macrophages to block immunosuppressive characteristics in

#### *Immune Checkpoint and Tumor Therapy DOI: http://dx.doi.org/10.5772/intechopen.107203*

melanoma bearing mice. Importantly, the combination of STING-NPs enhanced response to α-PD-1 and α-CTLA-4, prolonged the survival and inhibit tumor growth compared with ICT or free cGAMP-ICT treatment. These results confirmed that STING-NPs can activate STING pathways in myeloid cell populations in TME and increases the therapeutic efficacy of ICT.

#### *3.2.4 Other approaches to regulating immune-suppressive TME*

There are plenty of other immune suppressive mechanisms related with the reduced effectiveness of ICT. In view of this, several therapeutic agents have been applied to regulate various immune suppressive mechanisms and increase the efficacy of ICT, such as pro-stromal signaling modulators [36], exosome release inhibitors [37], tumor-associated myeloid cells (TAMCs) eliminators [38], TAMC recruitment inhibitors [39], and TAMC reprogrammers [40]. For instance, inhibiting C-X-C motif chemokine ligand 12 (CXCL12), which is secreted by CAFs and promotes cancer cell migration and proliferation, is another approach to regulate the fibrotic stroma. Shen et al. downregulated the CXCL12 expression by employing small trap proteins targeting IL-10 and CXCL12, leading to elevated tumor-infiltrating DCs, NK cells, and tumor-infiltrated T cells [36]. TLR7 and TLR8 are highly expressed in leukocytes and myeloid cells. Lee et al. revealed the treatment of TLR agonist resiquimod which binds to TLR7 and TLR8 can promote the differentiation of myeloid derived suppressor cells (MDSCs) into macrophages and dendritic cells [40]. MDSCs were shown to lost immunosuppressive ability in T cells and result in increased proliferation of T cells.

#### **3.3 Combine ICT with other therapies**

ICT can combine with other immunotherapies, such as cancer vaccines, to augment antitumor immunity. Moreover, conventional therapeutic approaches, including chemotherapy, phototherapy, radiotherapy, not only can kill cancer cells but also show immunomodulation effects. ICT can combine with these different treatments to boost the antitumor immunotherapeutic effects.
