Cited by 215Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesImmune cells in cancer

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Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

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Yang, Li, Li, Aitian, Lei, Qingyang, Zhang, Yi·2019·Journal of Hematology & Oncology

DOI 10.1186/s13045-019-0804-8PMC PMC6880373

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Abstract

Immunotherapy is a currently popular treatment strategy for cancer patients. Although recent developments in cancer immunotherapy have had significant clinical impact, only a subset of patients exhibits clinical response. Therefore, understanding the molecular mechanisms of immunotherapy resistance is necessary. The mechanisms of immune escape appear to consist of two distinct tumor characteristics: a decrease in effective immunocyte infiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment. Several host-derived factors may also contribute to immune escape. Moreover, inter-patient heterogeneity predominantly results from differences in somatic mutations between cancers, which has led to the hypothesis that differential activation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset of cancers. Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating the immunosuppressive tumor microenvironment and tumor immune escape. Therefore, understanding the mechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify new therapeutic targets for expanding the efficacy of cancer immunotherapies.

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Fig. 1 Tumor-intrinsic signaling induces the exclusion and dysfunction of effective immunocytes. Oncogenic drivers of tumors, including β-catenin, STAT3, PI3K/PTEN/AKT/mTOR, p53, NF-κB, and RAS/RAF/MAPK signaling, are activated in the tumor microenvironment. These oncogenic signaling pathways not only downregulate the production of chemokines, which further decrease the recruitment of DCs, macrophages, T cells, and NK cells to tumor sites, but also induce immunosuppression of these immunocytes. In addition, tumor-intrinsic signaling can induce PD-L1 expression in tumor cells, leading to T cell dysfunction in the tumor microenvironmentCC BY · PubMed Central

Fig. 2 Tumor-intrinsic signaling mediates the recruitment and differentiation of immunosuppressive cells. Oncogenic pathways in tumor cells can be activated to promote the production of several chemokines and cytokines, which further enhance the recruitment and polarization of immunosuppressive cells, such as TAMs, MDSCs, Tregs, and TANs, to tumor sites. These immunosuppressive cells within the tumor microenvironment may also contribute to immunoresistance in cancersCC BY · PubMed Central

Fig. 3 Tumor-intrinsic signaling as a therapeutic target for cancers. The activation of tumor-intrinsic signaling regulates and promotes the immunosuppressive tumor microenvironment, which includes exclusion and dysfunction of effective immunocytes and recruitment and differentiation of immunosuppressive cells. Therefore, targeting the tumor-intrinsic signaling is a potential strategy for cancer treatmentCC BY · PubMed Central

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See all 215

Authors: Yang, L., Li, A., Lei, Q., & Zhang, Y.
Affiliations: First Affiliated Hospital of Zhengzhou University (CN)
Zhengzhou University (CN)
Corresponding author: Zhang, Yi
ORCID: Yang, Li
Li, Aitian
Zhang, Yi
Venue: Journal of Hematology & Oncology
Publisher: Springer Science and Business Media LLC
Published: 2019-11-27
Volume: 12
Issue: 1
Pages: 125-125
ISSN: 1756-8722 (ISSN-L)
DOI: 10.1186/s13045-019-0804-8
PMC: PMC6880373
OpenAlex: W2990431514
Cited by: 215
References: 126
Citations by year: 2026: 27 · 2025: 40 · 2024: 29 · 2023: 31 · 2022: 39 · 2021: 28 · 2020: 20
FWCI: 2.07
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Journal of Hematology & Oncology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (U1804281, 81771781, 81602024)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: immunosuppressive tumor microenvironment, tumor immune evasion, cancer immunotherapy resistance, immune exclusion, interpatient heterogeneity, somatic mutations, immune cell infiltration, therapeutic target
MeSH terms: Antineoplastic Agents, Humans, Immunosuppressive Agents, Immunotherapy, Neoplasms, Signal Transduction, Tumor Escape, Molecular Targeted Therapy, Tumor Microenvironment

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Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

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