Immune checkpoints and cancer immunotherapies - insights into newly potential receptors and ligands

Sep 24, 2026

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Checkpoint markers and immune checkpoint inhibitors are increasingly developed as immunotherapeutic targets across human cancers. Despite efforts to identify novel immune checkpoints and their ligands, key questions remain regarding the exact therapeutic functions and the comprehensive mapping of corresponding receptors. Tumor microenvironment signaling can induce inhibitory receptors on T cells, promoting dysfunction or exhaustion. Clinical resistance often limits efficacy, motivating combination strategies targeting newly discovered inhibitory molecules and multiple checkpoints to improve outcomes.

LanguageEnglish

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Abstract

Introduction

Tumor-associated antigens and checkpoint signaling

T-cell dysfunction and checkpoint blockade

TherapeuTic advances in vaccines and immunotherapy Review | Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands
Ali N. Kamali, José M. Bautista, Michael Eisenhut and Haleh Hamedifar
Abstract: Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or coinhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and Band T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.
Keywords: cancers, checkpoints inhibitors and immunotherapy, immune checkpoints
Received: 23 October 2022; revised manuscript accepted: 14 July 2023. | | TherAdv Vaccines Immunother
2023, Vol. 11: 1–36
DOI: 10. 1177/ 25151355231192043 © The Author(s), 2023.
Article reuse guidelines: [sagepub.com/journals](sagepub.com/journals)permissions
Correspondence to:
Ali N. Kamali
CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Simin Dasht Industrial Area, Karaj, Iran
CinnaGen Research and Production Co. , Alborz 3165933155, Iran
[alin_kamali@yahoo.com](alin_kamali@yahoo.com); [kamalia@cinnagen.com](kamalia@cinnagen.com)
José M. Bautista
Department of Biochemistry and Molecular Biology, Faculty of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain Research Institute Hospital 12 de Octubre, Madrid, Spain
Michael Eisenhut
Department of Pediatrics, Luton and Dunstable University Hospital NHS Foundation Trust, Luton, UK
Haleh Hamedifar
CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
CinnaGen Research and Production Co. , Alborz, Iran | | --- | --- | --- | | Introduction
Tumor-associated antigens or immune checkpoint molecules play a pivotal role in the immune regulation of malignancies whose biological significance is crucial in cancer diagnosis, prognosis, and treatment. The checkpoints that are placed either on the surface of various immune cells including T lymphocytes or on tumor cells act like a switching protein through the induction of various signals to control the over-activation ofT cells. In can

FAQs

What roles do immune checkpoints play in cancer immune regulation?

Immune checkpoints function as switching proteins that control T-cell activation through co-stimulatory or co-inhibitory signals on immune and tumor cells. In cancers, persistent antigen exposure can drive inhibitory receptor overexpression and impair T-cell function.

Why do immune checkpoint inhibitor therapies often show limited long-term success?

Clinical efficacy varies because patients can develop de novo or adaptive resistance. This resistance reduces the overall effectiveness of single-agent checkpoint targeting.

How can new findings on receptors and ligands improve cancer immunotherapy strategies?

Identifying newly emerging checkpoints and their receptor counterparts can support more precise and effective therapy design. The review emphasizes combination approaches, including blocking multiple checkpoints or pairing with newly discovered inhibitory molecules, to address resistance.

Sep 24, 2026

Uploaded by Putri