In many solid tumor types, tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME). Moreover, TAMs infiltration is strongly associated with poor survival in solid tumor patients. In this review, we describe the origins of TAMs and their polarization state dictated by the TME. We also specifically focus on the role of TAMs in promoting tumor growth, enhancing cancer cells resistance to chemotherapy and radiotherapy, promoting tumor angiogenesis, inducing tumor migration and invasion and metastasis, activating immunosuppression. In addition, we discuss TAMs can be used as therapeutic targets of solid tumor in clinics. The therapeutic strategies include clearing macrophages and inhibiting the activation of TAMs, promoting macrophage phagocytic activity, limiting monocyte recruitment and other targeted TAMs therapies.

Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.

Tumor‐associated macrophages (TAMs) in solid tumors exert protumor activities by releasing cytokines or growth factors into the tumor microenvironment. Increasing studies have also shown that TAMs play a key role in tumor progression, such as tumor angiogenesis, immunosuppression, cell proliferation, migration, invasion, and metastasis. A large body of evidence shows that the abundance of TAMs in solid tumors is correlated with poor disease prognosis and resistance to therapies. Therefore, targeting TAMs in solid tumors is considered to be a promising immunotherapeutic strategy. At present, the therapeutic strategies of targeting macrophages mainly include limiting monocyte recruitment, depletion strategies, promoting macrophage phagocytic activity, and induction of macrophage reprogramming. Additionally, targeting TAMs in combination with conventional therapies has been demonstrated to be a promising therapeutic strategy in solid tumors. In the present review, we summarized various TAMs‐targeting therapeutic strategies for treating solid tumors. This review also discusses the challenges for targeting TAMs as tumor treatments, the obstacles in clinical trials, and the perspective for the future development of TAMs‐targeting therapies for various cancers.

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To explore the effects of RNA interference targeting four different genes (VEGF, C-myc, Survivin, hTERT) on the growth and proliferation of nasopharyngeal carcinoma (NPC) CNE-2Z cells. Fluorescein-labeled short-hairpin (sh)RNA plasmids together and separately targeting VEGF, C-myc, Survivin and hTERT were built and respectively called plasmid-shVEGF-shC-myc-shSurvivinshhTERT, plasmid-shVEGF, plasmid-shC-myc, plasmid-shSurvivin, plasmid-shhTERT. These plasmids were respectively transfected into human NPC CNE-2Z cells and xenograft tumors in nude mice. The expression of plasmids in NPC CNE-2Z cells and xenograft tumors was observed. Cell proliferation was detected with MTT assay. The mRNA and protein expression were determined by real-time PCR and western blot, respectively. The effects of plasmids on the biological behavior of CNE-2Z cells were observed with transwell invision chamber models. Apoptosis was determined with flow cytometer. The inhibitory effect of plasmids on xenograft tumors was observed in nude mice. The plasmid containing four different shRNAs could significantly inhibit CNE-2Z cell proliferation and decrease invasion ability in vitro compared with plasmids with each single shRNA (Po0.05). The plasmid containing four different shRNAs could simultaneously downregulate VEGF, C-myc, surviving, hTERT mRNA and protein expression in the CNE-2Z cells. The multiple gene shRNA could more significantly induce cell apoptosis than each single shRNA, respectively (Po0.05). The combinative silencing of these four genes had a better inhibitory effect on xenograft tumors than the silencing of each single shRNA (Po0.05). RNA interference targeting multiple genes can effectively inhibit NPC proliferation and induce apoptosis, which provides an experiment basis for NPC gene therapy.

Background Circadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single‐nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients. Methods Nine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan‐Meier curve were used for prognosis analysis. Results Among the nine SNPs, rs11133399 in CLOCK, rs1044432 and rs2279284 in BAML1 were significantly associated with GC overall survival and recurrence‐free survival. The unfavorable genotypes of these SNPs showed a cumulative effect on GC prognosis. Multivariate assessment model indicated that these SNPs, in conjunction with clinical variables, enhanced the power to predict GC prognosis. In addition, survival tree analysis revealed the genotype of rs11133399 as a primary risk factor contributing to the prognosis of GC patients. Functional assays showed that the G allele in rs11133399 significantly enhanced luciferase reporter activity than A allele. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, suggesting that this SNP might affect the prognosis of GC through its influence on the expression of CLOCK gene. Conclusions Our data indicate that SNPs in CPFL genes might contribute to the clinical outcome of GC through their impact on gene expression. Further studies are needed to elucidate its underlying molecular mechanisms.

Leigh syndrome (LS), the most common mitochondrial disease in early childhood, usually manifests variable neurodegenerative symptoms and typical brain magnetic resonance imaging (MRI) lesions. To date, pathogenic variants in more than 80 genes have been identified. However, there are still many cases without molecular diagnoses, and thus more disease-causing variants need to be unveiled. Here, we presented three clinically suspected LS patients manifesting neurological symptoms including developmental delay, hypotonia, and epilepsy during the first year of age, along with symmetric brain lesions on MRI. We explored disease-associated variants in patients and their nonconsanguineous parents by whole-exome sequencing and subsequent Sanger sequencing verification. Sequencing data revealed three pairs of diseaseassociated compound heterozygous variants: c.1A>G (p.Met1?) and 409G>C (p. Asp137His) in SDHA, c.1253G>A (p.Arg418His) and 1300C>T (p.Leu434Phe) in NARS2, and c.5C>T (p.Ala2Val) and 773T>G (p.Leu258Trp) in ECHS1. Among them, the likely pathogenic variants c.409G>C (p.Asp137His) in SDHA, c.1300C>T (p. Leu434Phe) in NARS2, and c.773T>G (p.Leu258Trp) in ECHS1 were newly identified. Segregation analysis indicated the possible disease-causing nature of the novel variants. In silico prediction and three-dimensional protein modeling further suggested the potential pathogenicity of these variants. Our discovery of novel variants expands the gene variant spectrum of LS and provides novel evidence for genetic counseling.