Cancer gene therapies are usually designed either to express wild-type copies of tumor suppressor genes or to exploit tumor-associated phenotypic changes to endow selective cytotoxicity. However, these approaches become less relevant to cancers that contain many independent mutations, and the situation is made more complex by our increased understanding of clonal evolution of tumors, meaning that different metastases and even regions of the same tumor mass have distinct mutational and phenotypic profiles. In contrast, the relatively genetically stable tumor microenvironment (TME) therefore provides an appealing therapeutic target, particularly since it plays an essential role in promoting cancer growth, immune tolerance, and acquired resistance to many therapies. Recently, a variety of different TME-targeted gene therapy and armed oncolytic strategies have been explored, with particular success observed in strategies targeting the cancer stroma, reducing tumor vasculature, and repolarizing the immunosuppressive microenvironment. Herein, we review the progress of these TME-targeting approaches and try to highlight those showing the greatest promise.

Background CD109 was involved in the tumorigenesis and progression of various cancers via TGF-β1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. Methods CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. Results IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. Conclusion Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.

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Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

Oncolytic viruses (OVs) provide the promise of tumor-selective cytotoxicity coupled with amplification of the therapeutic agent (the virus)in situwithin the tumor improving its therapeutic index. Despite this promise, however, single agent-treatments have not been as successful as combination therapies, particularly combining with checkpoint inhibitor antibodies. The antibodies may be delivered by two approaches, either encoded within the OV genome to restrict antibody production to sites of active virus infection or alternatively given alongside OVs as separate treatments. Both approaches have shown promising therapeutic outcomes, and this leads to an interesting question of whether one approach is potentially better than the other. In this review, we provide a brief summary of the combination OV-antibody therapies that target tumor cells, tumor microenvironment and immune cells to help define key parameters influencing which approach is superior, thereby improving insight into the rational design of OV treatment strategies.