Structure and functions of Mer, an innate immune checkpoint - Mini Review

Sep 24, 2026

Uploaded by Aran

Immunotherapy can help the body eliminate cancer cells, yet only a limited fraction of patients benefit in clinical practice. This review focuses on MerTK, an innate immune checkpoint in macrophages, explaining how macrophage Mer signaling contributes to immune suppression. It summarizes how pro-inflammatory M1 and anti-inflammatory M2 phenotypes shape tumor onset and progression. It also reviews preclinical and clinical evidence for Mer kinase inhibition to improve anti-tumor responses and patient outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Introduction

The role of macrophages in cancer progression

Mer is an innate immune checkpoint

Structural feature

Therapeutic targeting of MerTK

TYPE Mini Review PUBLISHED 23 October 2023 DOI 10.3389/fimmu.2023.1244170 OPEN ACCESS EDITED BY Alexandre P. A. Theocharides, University Hospital Zürich, Switzerland REVIEWED BY Rodwell Mabaera, Dartmouth Hitchcock Medical Center, United States Derek Brandon Oien, AstraZeneca, United States *CORRESPONDENCE Eric Ubil [ericubil@uab.edu](ericubil@uab.edu) RECEIVED 22 June 2023 ACCEPTED 09 October 2023 PUBLISHED 23 October 2023 CITATION Ubil E and Zahid KR (2023) Structure and functions of Mer, an innate immune checkpoint. Front. Immunol. 14:1244170 . doi: 10.3389/fimmu.2023.1244170 COPYRIGHT © 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. Structure and functions of Mer, an innate immune checkpoint Eric Ubil* and Kashif Raﬁq Zahid Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States Immunotherapy 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. KEYWORDS MerTK, macrophage, cancer, immune, MerTK inhibitors, clinical trials Introduction Over 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 (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. Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) The role of macrophages in cancer progression Though 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

FAQs

Why do immune checkpoint blockades have limited efficacy in many solid tumors?

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.

How do macrophage M1 and M2 phenotypes influence tumor progression?

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.

What is the role of Mer (MerTK) in macrophages and cancer?

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.

Sep 24, 2026

Uploaded by Aran