In contrast, cold tumors are poorly immunogenic, there are less lymphocyte infiltrations and more immune suppressing cells189

In contrast, cold tumors are poorly immunogenic, there are less lymphocyte infiltrations and more immune suppressing cells189. tumor microenvironment to improve cancer chemotherapy and immunotherapy. study, the nanomaterial showed promising results in inhibiting tumor metastasis. A key challenge in CAF research is the lack of simple nomenclature of CAFs and the fibroblast subtypes for broader use in cancer and stromal biology. There is also a lack of robust biomarkers for CAFs detections in the clinical setting120. Deeper understanding of the CAFs origin, diverse function, heterogeneity and plasticity will be beneficial in modulating CAFs for anti-cancer therapy120. The design of sophisticated nanoparticulate drug delivery systems targeting CAFs relies on a more fundamental understanding of CAFs. 2.5. Platelets Platelets are anucleate blood cells that are present in the tumor microenvironment. Besides their role in blood coagulation, platelets have been recognized for supporting tumor growth and metastasis121,122. Platelets interact with tumor cells through different ways. In brief, tumors relying on the vascular network for growth can induce aggregation, activation, and secretion of the platelets flowing through the tumor vessels122. Platelets not only protect tumor cells from blood sheer stress and immune cell-mediated elimination123, but also interact with other components in the tumor microenvironment, such as endothelial cells, pericytes, fibroblasts and immune cells thereby contributing to tumor progression and inflammation124. Targeting platelets using nanoparticle-based drug delivery systems can potentially inhibit tumor metastasis. For example Zhang et?al.125 designed nanoparticles modified with the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) to deliver platelet inhibitor (ticagrelor). These nanoparticles were determined to efficiently inhibit platelet-tumor cell interaction and block tumor cell transition into mesenchymal-like invasive cells in a mammary tumor xenograft mouse model. Interestingly, platelet drug-loading and platelet membrane biomimetic systems are also very popular Mouse monoclonal to NKX3A for tumor therapy126, 127, 128. Xu et?al.129 conjugated doxorubicin-loaded platelets with anti-CD22 monoclonal antibodies for tumor targeting. The platelet drug carriers prolonged the circulation time of doxorubicin. Enhanced antitumor activity was observed both and in response to microenvironmental signals, such as cytokines, chemokines, growth factors, as well as signals derived from other cells160. This process is called macrophage polarization. TAMs are usually M2 phenotype although they can exhibit either polarization phenotype161, 162, 163. The TAMs in the tumor microenvironment contribute to tumor progression, survival CF53 and metastasis and may result in a poor clinical outcome164. Targeting TAMs to prevent tumor progression and metastasis has become a promising anticancer strategy. TAM-targeted therapy is mainly focused on inhibition of macrophage recruitment165,166, elimination of M2-TAMs167 or re-polarization of M2-TAMs to M1-TAMs168,169. For example, Das et?al.170 reported a pancreatic cancer therapy involving activation of the innate immune receptor retinoic acid-inducible gene 1 (RIG-1) by a short interfering RNA agonist using surface-modified nanoparticles. This resulted in a higher M1:M2 macrophage ratio, increased proportion of cytotoxic T cells over regulatory T cells, as well as a reduction in regulatory B cells and plasma cells. Rong et?al.171 introduced Fe3+ into PEGylated polydopamine to form iron chelated nanoparticles (Fe@PDA-PEG). As shown in Fig.?2, Fe@PDA-PEG nanoparticles induced M2-TAMs to M1 repolarization and enhanced anti-tumor efficacy in colon carcinoma and breast carcinoma mouse models. Pang et?al.172 developed PLGA nanoparticles that were coated with M2-macrophages binding peptide (M2pep) to encapsulate PLX3397, a receptor tyrosine kinase inhibitor that was shown to deplete macrophages in tumors173. Results showed an increased uptake of M2pep-coated PLGA CF53 nanoparticles in M2-TAMs and reduced tumor growth in a mouse melanoma model. Open in a separate window Figure?2 Iron chelated melanin like nanoparticles (Fe@PDA-PEG) induced M2-TAMs to M1 repolarization. Combining with photothermal therapy (PTT)-induced tumor-associated antigens (TAAs) release altered the tumor microenvironment to immune-induced cancer cell killing mode. (M, macrophages; MHC II, major histocompatibility complex class II; TCR, T cell receptor). Reprinted with the permission from Ref.?171. Copyright ? 2019 Elsevier. 3.2. Chronic inflammation in tumor development Chronic inflammation is critically related to tumor progression174. On the one hand, cancers may arise from sites of infection and chronic inflammation, such as colorectal cancer associated with inflammatory bowel disease175 and esophageal adenocarcinoma associated with reflux esophagitis176. On the other hand, tumor progression can often lead to chronic inflammation due to the inflammatory cytokines or other inflammatory stimuli177. In the tumor microenvironment, cytokines such as tumor necrosis factor (TNF-(TGFand IL-10, are accumulated in the tumor microenvironment183. These cytokines are involved in a variety of activities in CF53 tumorigenesis and play important roles in the chronic inflammation processes184,185. Combinations of inflammation modulating agents can improve the efficacy.