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A. Theocharides, University Hospital Zürich, Switzerland  \nREVIEWED BY  \nRodwell Mabaera,  \nDartmouth Hitchcock Medical Center, United States  \nDerek Brandon Oien,  \nAstraZeneca, United States  \n*CORRESPONDENCE Eric Ubil  \n [ericubil@uab.edu](ericubil@uab.edu)  \nRECEIVED 22 June 2023  \nACCEPTED 09 October 2023  \nPUBLISHED 23 October 2023  \nCITATION  \nUbil E and Zahid KR (2023) Structure and functions of Mer, an innate immune checkpoint.  \nFront. Immunol. 14:1244170 .  \ndoi: 10.3389/fimmu.2023.1244170  \nCOPYRIGHT  \n© 2023 Ubil and Zahid. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nStructure and functions of Mer, an innate immune checkpoint  \nEric Ubil* and Kashif Rafiq Zahid  \nDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States  \nImmunotherapy is a promising therapeutic tool that promotes the elimination of cancerous cells by a patient’s own immune system. However, in the clinical setting, the number of cancer patients benefitting from immunotherapy is limited. Identification and targeting of other immune subsets, such as tumorassociated macrophages, and alternative immune checkpoints, like Mer, may further limit tumor progression and therapy resistance. In this review, we highlight the key roles of macrophage Mer signaling in immune suppression. We also summarize the role of pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in tumor onset and progression and how Mer structure and activation can be targeted therapeutically to alter activation state. Preclinical and clinical studies focusing on Mer kinase inhibition have demonstrated the potential of targeting this innate immune checkpoint, leading to improved anti-tumor responses and patient outcomes.  \nKEYWORDS  \nMerTK, macrophage, cancer, immune, MerTK inhibitors, clinical trials  \nIntroduction  \nOver the last 50 years, the 5-year survival rates of patients with most forms of cancer have improved by more than 15% . However, cancer remains the second leading cause of death in the United States and a leading cause of death worldwide (1) . While improvements in diagnosis and treatment have driven increased patient survival, it is clear that further advances are necessary. In recent years, immunotherapies, such as those targeting the adaptive immune response, have improved survival for patients with some forms of cancer  \n(2) . Unfortunately, checkpoint blockade has limited efficacy for the treatment of several solid tumors (3, 4) with the success of therapy correlated with overall tumor mutational burden (5) . Despite current limits of efficacy, approximately 44% of cancer patients in the United States are eligible for, or have received, immune checkpoint blockade (ICB) therapy. However only 13% of all cancer patients will respond (6) . The reasons for the low response rates are still under investigation, but clinical data demonstrates the therapeutic potential of targeting immune checkpoints.  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \nThe role of macrophages in cancer progression  \nThough innate immune cell targeted therapies lag behind adaptive immunotherapies in the clinic (7), there are well established roles for cells like macrophages in tumor progression. Often one of the most populous intra-tumoral immune cell subsets (8), macrophages are known to adopt pro-inflammatory (M1) or pro-wound healing (M2) phenotypes in the tumor environment. Single cell RNA sequencing has shown that the classic","cbCaif8PkDLmg49X","https://ap.wps.com/l/cbCaif8PkDLmg49X","pdf",965143,"English","# Introduction\n# The role of macrophages in cancer progression\n# Mer is an innate immune checkpoint\n# Structural feature\n# Therapeutic targeting of MerTK","[{\"question\":\"Why do immune checkpoint blockades have limited efficacy in many solid tumors?\",\"answer\":\"Checkpoint blockade efficacy is limited for several solid tumors, and success is correlated with tumor mutational burden. Only a minority of all cancer patients respond to ICB therapy.\"},{\"question\":\"How do macrophage M1 and M2 phenotypes influence tumor progression?\",\"answer\":\"M2 macrophages are linked to faster tumor progression, poorer outcomes, and resistance to adaptive immunotherapy, while M1 macrophages can directly restrict tumor growth through reactive oxygen species and coordination of anti-tumor immune responses via inflammatory cytokines.\"},{\"question\":\"What is the role of Mer (MerTK) in macrophages and cancer?\",\"answer\":\"MerTK is described as an innate immune checkpoint in macrophages. Cancer can target MerTK to limit anti-tumor immune responses, and the review discusses Mer structure, activation, and how it can be therapeutically targeted.\"}]","Structure and functions of Mer, an innate immune checkpoint - Mini Review | PDF",1790229769]