[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-383446-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-383446-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","harnessing-epithelial-mesenchymal-plasticity-to-boost-cancer-immunotherapy","Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy","","Immune checkpoint blockade (ICB) can reactivate T-cell anti-tumor responses, yet many patients experience primary or acquired resistance. This review identifies tumor epithelial–mesenchymal plasticity (EMP) as a critical driver of immune escape and immunotherapy resistance, summarizing tumor-intrinsic and tumor-extrinsic mechanisms. It outlines how tumors use EMP to promote immunosuppression, and discusses approaches to modulate EMP to reduce immune resistance while improving ICB therapeutic efficiency in cancer 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to boost cancer immunotherapy  \nYuanzhuo Gu1,4, Zhengkui Zhang2,3,4 and Peter ten Dijke1 ✉  \n© The Author(s) 2023  \n|  |  |  |\n| --- | --- | --- |\n| Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients. |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  | Keywords: Epithelial-to-mesenchymal plasticity (EMP); immune checkpoint blockade (ICB); immunotherapy resistance; tumor |  |\n|  |  |  |\n| microenvironment (TME) |  |  |\n|  | Cellular & Molecular Immunology (2023) 20:318–340; [https://doi.org/10.1038/s41423-023-00980-8](https://doi.org/10.1038/s41423-023-00980-8) |  |\n|  |  |  |\n\nINTRODUCTION  \nThe advent of immune checkpoint blockade (ICB) therapies, which (re)activate the T-cell mediated anti-tumor response [1], have demonstrated high clinical efficacy in some patients with difficultto-treat cancers and even in patients with metastasis [2–7] . The US Food and Drug Administration (FDA) has approved eight immune checkpoint inhibitors thus far, including one cytotoxic T-lymphocyte antigen-4 (CTLA-4) mAb (ipilimumab), three programmed death-1 (PD-1) monoclonal antibodies (mAbs; nivolumab, pembrolizumab, and cemiplimab), three programmed death-1 ligand 1(PD-L1) mAbs (atezolizumab, durvalumab, andavelumab) and one lymphocyte activation gene-3 (LAG-3) mAb (relatlimab), and more ICBs are being tested in clinical trials [8–10] . Collective analysis of clinical studies for anti-PD-1 or anti-PD-L1 monotherapy revealed that the objective response rates (ORRs) vary across different cancer types and subtypes. In some tumors (e.g., melanoma, Merkel cell carcinoma, and Hodgkin’s lymphoma), ICB therapies achieve high ORRs ranging from ~40% to 70%, while in the majority of tumor types, the ORRs are less than 25% [8, 11–13] . Apparently, clinical success occurs in only a minority of patients; most patients do not respond to ICBs. Patients who never respond to treatment are described as having primary resistance, and patients who initially respond but fail to achieve a long-term, durable response and eventually relapse are described as having acquired resistance [14, 15] . Considering the unmet medical need, delineating the nature of the resistance mechanisms and optimizing the targeting of novel mediators could help refine and improve immunotherapy treatment goals [16–18] .  \nTumor epithelial–mesenchymal plasticity (EMP), which refers to the ability of cancer cells to undergo a dynamic and reversible morphological switch from epithelial-like cells to fully or partially mesenchymal-like cells (termed epithelial to mesenchymal transition (EMT), or from mesenchymal-like cells to fully or partially epithelial-like cells (termed mesenchymal to epithelial transition (MET) [19–22], has been identified as a critical determinant of cancer progression [23, 24] . EMP/EMT has been linked to cancer cell stemness, metastasis, chemotherapy resistance and immunosuppression [24–26] . Additionally, regarding ICB therapy, EMP has emerged as a potential mediator of immunotherapy resistance [27–31] . Here, we review recent emerging studies about the interplay between EMP and immunotherapy resistance, and in particular focu","cbCaitsPa82Xf3MC","https://ap.wps.com/l/cbCaitsPa82Xf3MC","pdf",3801614,23,"English","# Introduction\n# EMP","[{\"question\":\"Why do many patients fail to benefit durably from immune checkpoint blockade (ICB)?\",\"answer\":\"Most patients do not respond or do not achieve durable responses due to primary or acquired ICB resistance, which limits clinical effectiveness.\"},{\"question\":\"What role does epithelial–mesenchymal plasticity (EMP) play in immunotherapy resistance?\",\"answer\":\"Tumor EMP is described as a critical determinant of immune escape and immunotherapy resistance, helping tumors establish immunosuppression.\"},{\"question\":\"How does the review propose improving ICB therapy outcomes?\",\"answer\":\"By outlining strategies to modulate tumor EMP to alleviate immune resistance and enhance the efficiency of ICB therapy.\"}]","Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy | PDF",1790257079,58]